157 results on '"Charles K. Meshul"'
Search Results
2. Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
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Allison J. Schaser, Teresa L. Stackhouse, Leah J. Weston, Patrick C. Kerstein, Valerie R. Osterberg, Claudia S. López, Dennis W. Dickson, Kelvin C. Luk, Charles K. Meshul, Randall L. Woltjer, and Vivek K. Unni
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Synucleinopathies ,Parkinson’s disease ,Dementia with Lewy bodies ,Alpha-synuclein ,Lewy body ,Trans-synaptic spread ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson’s disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models. This new model allows rigorous study of the initial location of Lewy pathology formation and propagation in the living brain, and strongly suggests that aggregation begins in axonal structures with retrograde propagation to the cell body. This model also shows expeditious development of alpha-synuclein pathology following induction with small, in vitro-generated alpha-synuclein pre-formed fibrils (PFFs), as well as accelerated cell death of inclusion-bearing cells. Using this model, we found that aggregated alpha-synuclein somatic inclusions developed first in neurons, but later showed a second wave of inclusion formation in astrocytes. Interestingly, astrocytes appear to survive much longer after inclusion formation than their neuronal counterparts. This model also allowed careful study of peripheral-to-central spread of Lewy pathology after PFF injection into the hind limb musculature. Our results clearly show evidence of progressive, retrograde trans-synaptic spread of Lewy pathology through known neuroanatomically connected pathways in the motor system. As such, we have developed a promising tool to understand the biology of neurodegeneration associated with alpha-synuclein aggregation and to discover new treatments capable of altering the neurodegenerative disease course of synucleinopathies.
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- 2020
- Full Text
- View/download PDF
3. Aged xCT-Deficient Mice Are Less Susceptible for Lactacystin-, but Not 1-Methyl-4-Phenyl-1,2,3,6- Tetrahydropyridine-, Induced Degeneration of the Nigrostriatal Pathway
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Eduard Bentea, Laura De Pauw, Lise Verbruggen, Lila C. Winfrey, Lauren Deneyer, Cynthia Moore, Giulia Albertini, Hideyo Sato, Ann Van Eeckhaut, Charles K. Meshul, and Ann Massie
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glutamate ,neuroprotection ,aging ,proteasome inhibition ,Parkinson’s disease ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The astrocytic cystine/glutamate antiporter system xc– (with xCT as the specific subunit) imports cystine in exchange for glutamate and has been shown to interact with multiple pathways in the brain that are dysregulated in age-related neurological disorders, including glutamate homeostasis, redox balance, and neuroinflammation. In the current study, we investigated the effect of genetic xCT deletion on lactacystin (LAC)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced degeneration of the nigrostriatal pathway, as models for Parkinson’s disease (PD). Dopaminergic neurons of adult xCT knock-out mice (xCT–/–) demonstrated an equal susceptibility to intranigral injection of the proteasome inhibitor LAC, as their wild-type (xCT+/+) littermates. Contrary to adult mice, aged xCT–/– mice showed a significant decrease in LAC-induced degeneration of nigral dopaminergic neurons, depletion of striatal dopamine (DA) and neuroinflammatory reaction, compared to age-matched xCT+/+ littermates. Given this age-related protection, we further investigated the sensitivity of aged xCT–/– mice to chronic and progressive MPTP treatment. However, in accordance with our previous observations in adult mice (Bentea et al., 2015a), xCT deletion did not confer protection against MPTP-induced nigrostriatal degeneration in aged mice. We observed an increased loss of nigral dopaminergic neurons, but equal striatal DA denervation, in MPTP-treated aged xCT–/– mice when compared to age-matched xCT+/+ littermates. To conclude, we reveal age-related protection against proteasome inhibition-induced nigrostriatal degeneration in xCT–/– mice, while xCT deletion failed to protect nigral dopaminergic neurons of aged mice against MPTP-induced toxicity. Our findings thereby provide new insights into the role of system xc– in mechanisms of dopaminergic cell loss and its interaction with aging.
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- 2021
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- View/download PDF
4. Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism
- Author
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Leah J. Weston, Anna M. Bowman, Valerie R. Osterberg, Charles K. Meshul, Randall L. Woltjer, and Vivek K. Unni
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Lewy pathology ,nuclear inclusions ,multiphoton imaging ,nuclear rods ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.
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- 2022
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5. Early life sleep disruption alters glutamate and dendritic spines in prefrontal cortex and impairs cognitive flexibility in prairie voles
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Carolyn E. Jones, Alex Q. Chau, Randall J. Olson, Cynthia Moore, Peyton T. Wickham, Niyati Puranik, Marina Guizzetti, Hung Cao, Charles K. Meshul, and Miranda M. Lim
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Development ,Extinction ,Autism ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Early life experiences are crucial for proper organization of excitatory synapses within the brain, with outsized effects on late-maturing, experience-dependent regions such as the medial prefrontal cortex (mPFC). Previous work in our lab showed that early life sleep disruption (ELSD) from postnatal days 14–21 in the highly social prairie vole results in long lasting impairments in social behavior. Here, we further hypothesized that ELSD alters glutamatergic synapses in mPFC, thereby affecting cognitive flexibility, an mPFC-dependent behavior. ELSD caused impaired cued fear extinction (indicating cognitive inflexibility), increased dendritic spine density, and decreased glutamate immunogold-labeling in vesicular glutamate transporter 1 (vGLUT1)-labeled presynaptic nerve terminals within mPFC. Our results have profound implications for neurodevelopmental disorders in humans such as autism spectrum disorder that also show poor sleep, impaired social behavior, cognitive inflexibility, as well as altered dendritic spine density and glutamate changes in mPFC, and imply that poor sleep may cause these changes.
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- 2021
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6. Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice
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Jack C. Reidling, Aroa Relaño-Ginés, Sandra M. Holley, Joseph Ochaba, Cindy Moore, Brian Fury, Alice Lau, Andrew H. Tran, Sylvia Yeung, Delaram Salamati, Chunni Zhu, Asa Hatami, Carlos Cepeda, Joshua A. Barry, Talia Kamdjou, Alvin King, Dane Coleal-Bergum, Nicholas R. Franich, Frank M. LaFerla, Joan S. Steffan, Mathew Blurton-Jones, Charles K. Meshul, Gerhard Bauer, Michael S. Levine, Marie-Francoise Chesselet, and Leslie M. Thompson
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Huntington's disease ,neural stem cell ,transplantation ,R6/2 mice ,Q140 mice ,embryonic stem cells ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Summary: Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies.
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- 2018
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7. Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease
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Anna Parievsky, Cindy Moore, Talia Kamdjou, Carlos Cepeda, Charles K. Meshul, and Michael S. Levine
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Huntington's disease ,Thalamus ,R6/2 ,Medium-sized spiny neurons ,Optogenetics ,Electron microscopy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington's disease (HD) is a fatal genetic disorder characterized by cell death of medium-sized spiny neurons (MSNs) in the striatum, traditionally attributed to excessive glutamate inputs and/or receptor sensitivity. While changes in corticostriatal projections have typically been studied in mouse models of HD, morphological and functional alterations in thalamostriatal projections have received less attention. In this study, an adeno-associated virus expressing channelrhodopsin-2 under the calcium/calmodulin-dependent protein kinase IIα promoter was injected into the sensorimotor cortex or the thalamic centromedian-parafascicular nuclear complex in the R6/2 mouse model of HD, to permit selective activation of corticostriatal or thalamostriatal projections, respectively. In symptomatic R6/2 mice, peak amplitudes and areas of corticostriatal glutamate AMPA and NMDA receptor-mediated responses were reduced. In contrast, although peak amplitudes of AMPA and NMDA receptor-mediated thalamostriatal responses also were reduced, the areas remained unchanged due to an increase in response decay times. Blockade of glutamate reuptake further increased response areas and slowed rise and decay times of NMDA responses. These effects appeared more pronounced at thalamostriatal synapses of R6/2 mice, suggesting increased activation of extrasynaptic NMDA receptors. In addition, the probability of glutamate release was higher at thalamostriatal than corticostriatal synapses, particularly in R6/2 mice. Morphological studies indicated that the density of all excitatory synaptic contacts onto MSNs was reduced, which matches the basic electrophysiological findings of reduced amplitudes. There was a consistent reduction in the area of spines but little change in presynaptic terminal size, indicating that the postsynaptic spine may be more significantly affected than presynaptic terminals. These results highlight the significant and differential contribution of the thalamostriatal projection to glutamate excitotoxicity in HD.
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- 2017
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8. Effects of Sub-Chronic MPTP Exposure on Behavioral and Cognitive Performance and the Microbiome of Wild-Type and mGlu8 Knockout Female and Male Mice
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Eileen Ruth S. Torres, Tunde Akinyeke, Keaton Stagaman, Robert M. Duvoisin, Charles K. Meshul, Thomas J. Sharpton, and Jacob Raber
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Parkinson’s disease ,metabotropic glutamate receptor ,behavioral performance ,gut microbiome ,tyrosine hydroxylase ,beta actin ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Motor dysfunction is a hallmark of Parkinson’s disease (PD); however, non-motor symptoms such as gastrointestinal dysfunction often arise prior to motor symptoms. Alterations in the gut microbiome have been proposed as the earliest event in PD pathogenesis. PD symptoms often demonstrate sex differences. Glutamatergic neurotransmission has long been linked to PD pathology. Metabotropic glutamate receptors (mGlu), a family of G protein-coupled receptors, are divided into three groups, with group III mGlu receptors mainly localized presynaptically where they can inhibit glutamate release in the CNS as well as in the gut. Additionally, the gut microbiome can communicate with the CNS via the gut-brain axis. Here, we assessed whether deficiency of metabotropic glutamate receptor 8 (mGlu8), group III mGlu, modulates the effects of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on behavioral and cognitive performance in female and male mice. We studied whether these effects are associated with changes in striatal tyrosine hydroxylase (TH) levels and the gut microbiome. Two-week sub-chronic MPTP increased activity of female and male wild-type (WT) and mGlu8 knockout (KO) mice in the open field. MPTP also showed genotype- and sex-dependent effects. MPTP increased the time WT, but not KO, females and males spent exploring objects. In WT mice, MPTP improved sensorimotor function in males but impaired it in females. Further, MPTP impaired cued fear memory in WT, but not KO, male mice. MPTP reduced striatal TH levels in WT and KO mice but these effects were only pronounced in males. MPTP treatment and genotype affected the diversity of the gut microbiome. In addition, there were significant associations between microbiome α-diversity and sensorimotor performance, as well as microbiome composition and fear learning. These results indicate that specific taxa may directly affect motor and fear learning or that the same physiological effects that enhance both forms of learning also alter diversity of the gut microbiome. MPTP’s effect on motor and cognitive performance may then be, at least in part, be mediated by the gut microbiome. These data also support mGlu8 as a novel therapeutic target for PD and highlight the importance of including both sexes in preclinical studies.
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- 2018
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9. Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease
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Philippe Thuillier, P. Hemachandra Reddy, Charles K. Meshul, and Peizhong Mao
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cocaine- and amphetamine- regulated transcript ,mitochondria ,antioxidant ,dopamine ,oxidative stress ,neuroprotection ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript), a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics.
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- 2013
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10. Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease
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Natalie R.S. Goldberg, Victoria Fields, Lacey Pflibsen, Michael F. Salvatore, and Charles K. Meshul
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Dopamine ,Striatum ,MPTP ,Social enrichment ,Tyrosine hydroxylase ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute l-DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute l-DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration.
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- 2012
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11. Unraveling the central proopiomelanocortin neural circuits
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Aaron J. Mercer, Shane T. Hentges, Charles K. Meshul, and Malcolm J. Low
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Arcuate Nucleus ,Hypothalamus ,Metabolism ,neural networks ,energy homeostasis ,proopiomelanocortin neurons ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: How and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.
- Published
- 2013
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12. Early life sleep disruption alters glutamate and dendritic spines in prefrontal cortex and impairs cognitive flexibility in prairie voles
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Miranda M. Lim, Niyati Puranik, Cynthia Moore, Alex Q. Chau, Marina Guizzetti, Randall Olson, Carolyn E. Jones, Hung Cao, Charles K. Meshul, and Peyton Teutsch Wickham
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Dendritic spine ,biology ,Vesicular glutamate transporter 1 ,Autism ,General Engineering ,Cognitive flexibility ,Glutamate receptor ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Extinction (psychology) ,Extinction ,Development ,biology.organism_classification ,Prairie vole ,Glutamatergic ,biology.protein ,Prefrontal cortex ,Neuroscience ,RC321-571 - Abstract
Early life experiences are crucial for proper organization of excitatory synapses within the brain, with outsized effects on late-maturing, experience-dependent regions such as the medial prefrontal cortex (mPFC). Previous work in our lab showed that early life sleep disruption (ELSD) from postnatal days 14–21 in the highly social prairie vole results in long lasting impairments in social behavior. Here, we further hypothesized that ELSD alters glutamatergic synapses in mPFC, thereby affecting cognitive flexibility, an mPFC-dependent behavior. ELSD caused impaired cued fear extinction (indicating cognitive inflexibility), increased dendritic spine density, and decreased glutamate immunogold-labeling in vesicular glutamate transporter 1 (vGLUT1)-labeled presynaptic nerve terminals within mPFC. Our results have profound implications for neurodevelopmental disorders in humans such as autism spectrum disorder that also show poor sleep, impaired social behavior, cognitive inflexibility, as well as altered dendritic spine density and glutamate changes in mPFC, and imply that poor sleep may cause these changes.
- Published
- 2022
13. Microwave Brain Tissue Processing: Making Life Easier for Ultrastructural Immunohistochemical Analysis of Synapses in Rodent Models of Neurodegeneration
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Cynthia Moore and Charles K Meshul
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Instrumentation - Published
- 2022
14. Trans-synaptic and retrograde axonal spread of Lewy pathology following pre-formed fibril injection in an in vivo A53T alpha-synuclein mouse model of synucleinopathy
- Author
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Randall L. Woltjer, Claudia S. López, Charles K. Meshul, Allison J. Schaser, Teresa L. Stackhouse, Kelvin C. Luk, Valerie R. Osterberg, Leah J. Weston, Vivek K. Unni, Patrick C. Kerstein, and Dennis W. Dickson
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Male ,0301 basic medicine ,Genetically modified mouse ,Parkinson's disease ,Synucleinopathies ,Somatic cell ,Dementia with Lewy bodies ,Mice, Transgenic ,Biology ,lcsh:RC346-429 ,Pathology and Forensic Medicine ,Alpha-synuclein ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Humans ,Neurodegeneration ,lcsh:Neurology. Diseases of the nervous system ,Neurons ,Lewy body ,Research ,Brain ,medicine.disease ,Axons ,Disease Models, Animal ,Protein Transport ,030104 developmental biology ,chemistry ,Astrocytes ,Parkinson’s disease ,Trans-synaptic spread ,Female ,Lewy Bodies ,Neurology (clinical) ,Neuroscience ,030217 neurology & neurosurgery - Abstract
It is necessary to develop an understanding of the specific mechanisms involved in alpha-synuclein aggregation and propagation to develop disease modifying therapies for age-related synucleinopathies, including Parkinson’s disease and Dementia with Lewy Bodies. To adequately address this question, we developed a new transgenic mouse model of synucleinopathy that expresses human A53T SynGFP under control of the mouse prion protein promoter. Our characterization of this mouse line demonstrates that it exhibits several distinct advantages over other, currently available, mouse models. This new model allows rigorous study of the initial location of Lewy pathology formation and propagation in the living brain, and strongly suggests that aggregation begins in axonal structures with retrograde propagation to the cell body. This model also shows expeditious development of alpha-synuclein pathology following induction with small, in vitro-generated alpha-synuclein pre-formed fibrils (PFFs), as well as accelerated cell death of inclusion-bearing cells. Using this model, we found that aggregated alpha-synuclein somatic inclusions developed first in neurons, but later showed a second wave of inclusion formation in astrocytes. Interestingly, astrocytes appear to survive much longer after inclusion formation than their neuronal counterparts. This model also allowed careful study of peripheral-to-central spread of Lewy pathology after PFF injection into the hind limb musculature. Our results clearly show evidence of progressive, retrograde trans-synaptic spread of Lewy pathology through known neuroanatomically connected pathways in the motor system. As such, we have developed a promising tool to understand the biology of neurodegeneration associated with alpha-synuclein aggregation and to discover new treatments capable of altering the neurodegenerative disease course of synucleinopathies. Electronic supplementary material The online version of this article (10.1186/s40478-020-01026-0) contains supplementary material, which is available to authorized users.
- Published
- 2020
15. Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter
- Author
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Pauline Janssen, Laurence Ris, Ann Massie, Charles K. Meshul, Olaya Lara, Lutgarde Arckens, Emmanuel Hermans, Robert E. McCullumsmith, Lise Verbruggen, Madeline J Churchill, Hideyo Sato, Noemi Declerck, Adam J. Funk, Cynthia Moore, Sinead M. O’Donovan, Eduard Bentea, Laura De Pauw, Agnès Villers, Erica A K DePasquale, UCL - SSS/IONS/CEMO - Pôle Cellulaire et moléculaire, Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, Supporting clinical sciences, and Neuro-Aging & Viro-Immunotherapy
- Subjects
Proteomics ,0301 basic medicine ,Biochemistry & Molecular Biology ,Dendritic spine ,Autism Spectrum Disorder ,XCT ,TIME-DEPENDENT CHANGES ,Social Interaction ,Glutamic Acid ,PREFRONTAL CORTEX ,Striatum ,BEHAVIORS ,Neurotransmission ,Medium spiny neuron ,Antiporters ,Article ,Mice ,GLUTAMATE ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Postsynaptic potential ,Animals ,OXIDATIVE STRESS ,AUTISM ,SYSTEM X(C)(-) ,Molecular Biology ,Psychiatry ,Science & Technology ,IDENTIFICATION ,Chemistry ,Neurosciences ,Glutamate receptor ,MOUSE MODEL ,Cell biology ,Psychiatry and Mental health ,Electrophysiology ,030104 developmental biology ,Excitatory postsynaptic potential ,Cystine ,Neurosciences & Neurology ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery - Abstract
The astrocytic cystine/glutamate antiporter system xc− represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc−, xCT (xCT−/− mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT−/− mice. A proteomic and kinomic screen of the striatum of xCT−/− mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT−/− mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc− plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.
- Published
- 2020
16. Gait Deficits and Loss of Striatal Tyrosine Hydroxlase/Trk-B are Restored Following 7,8-Dihydroxyflavone Treatment in a Progressive MPTP Mouse Model of Parkinson’s Disease
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Cynthia Moore, Michelle S. Massaquoi, William A. Liguore, Madeline J Churchill, Charles K. Meshul, and Heather L. Melrose
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0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Substantia nigra ,Striatum ,Tropomyosin receptor kinase B ,7,8-Dihydroxyflavone ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Parkinsonian Disorders ,Dopamine ,Internal medicine ,Animals ,Medicine ,Gait ,Tyrosine hydroxylase ,business.industry ,General Neuroscience ,MPTP ,virus diseases ,Parkinson Disease ,Flavones ,medicine.disease ,Corpus Striatum ,Mice, Inbred C57BL ,Substantia Nigra ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,nervous system ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Tyrosine ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Parkinson’s disease (PD) is caused by neurodegeneration of nigrostriatal neurons, resulting in dopamine (DA) stimulated motor deficits. Like brain derived neurotrophic factor (BDNF), 7,8-dihydroxyflavone (DHF) is an agonist of the tropomyosin receptor kinase-B (TrkB) and stimulates the same secondary cascades that promote neuronal growth, survival and differentiation. We used our progressive mouse model of PD by administering increasing doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) over 4 weeks (5 days/week), and then treated mice with DHF for 4 weeks after the cessation of the toxin injections (i.e., restoration). Mice treated with DHF recovered motorically, even after MPTP administration. Despite a 75% loss of tyrosine hydroxylase (TH) expression in the dorsolateral (DL) striatum in the MPTP group, mice treated with DHF had a recovery comparable to that found in the respective control. There was no recovery of DA tissue levels within the DL striatum. In both the DL striatum and substantia nigra (SN)/midbrain, phosphorylated TrkB and secondary messengers were significantly increased following DHF compared to the MPTP only group. Expression of the sprouting biomarker, superior cervical ganglion 10 (SCG10), was increased ∼20% in the DL striatum and 66% in the SN/midbrain in mice treated with DHF compared to the MPTP only group. We report that after 4 weeks of progressive MPTP administration, DHF can restore motor deficits and TH within the DL striatum in a TrkB-dependent manner. Our data suggests that DHF may help alleviate motor symptoms of PD and restore the loss of DA terminals within the striatum.
- Published
- 2020
17. NG2 glia-derived GABA release tunes inhibitory synapses and contributes to stress-induced anxiety
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Cynthia Moore, Wei-Guang Li, Charles K. Meshul, Shumin Duan, Huifang Lou, Yao Liu, Xin Qi, Xiao Zhang, Yabing Yang, Yanfei Han, Xiao-Ping Tong, Tian-Le Xu, Xiaoqi Hong, and Xia Li
- Subjects
Male ,Cell type ,Patch-Clamp Techniques ,Vesicle-Associated Membrane Protein 2 ,Science ,Glutamate decarboxylase ,General Physics and Astronomy ,Mice, Transgenic ,Anxiety ,Hippocampal formation ,Neurotransmission ,Molecular neuroscience ,Inhibitory postsynaptic potential ,Hippocampus ,Synaptic Transmission ,Exocytosis ,Article ,General Biochemistry, Genetics and Molecular Biology ,Photostimulation ,Social Defeat ,Social defeat ,Mice ,Interneurons ,Animals ,Humans ,gamma-Aminobutyric Acid ,Oligodendrocyte Precursor Cells ,Multidisciplinary ,Glutamate Decarboxylase ,Chemistry ,Glial biology ,Cell Differentiation ,General Chemistry ,Disease Models, Animal ,nervous system ,Synapses ,Neuroscience ,Stress, Psychological - Abstract
NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers anxiety-like behavior in vivo and contributes to chronic social defeat stress., Nerve/glial antigen 2 (NG2) glia can sense synaptic inputs from neurons. Here, the authors show NG2 glia form functional GABAergic synapses by regulating inhibitory synaptic transmission onto adjacent hippocampal interneurons, and activation of NG2 glia induces anxiety-like behaviour in a mouse model of chronic social defeat stress.
- Published
- 2021
18. Changes in glucocorticoid receptor sensitivity following long‐term ethanol self‐administration in male and female rhesus macaques
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Vanessa A. Jimenez, Charles K. Meshul, Verginia C. Cuzon Carlson, and Kathleen A. Grant
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medicine.medical_specialty ,Ethanol ,business.industry ,Biochemistry ,Term (time) ,chemistry.chemical_compound ,Glucocorticoid receptor ,Endocrinology ,chemistry ,Internal medicine ,Genetics ,medicine ,Sensitivity (control systems) ,Self-administration ,business ,Molecular Biology ,Biotechnology - Published
- 2021
19. Glatiramer Acetate Reverses Motor Dysfunction and the Decrease in Tyrosine Hydroxylase Levels in a Mouse Model of Parkinson's Disease
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Cynthia Moore, Ella A. Kasanga, Mark A. Cantu, Michael F. Salvatore, Madeline J Churchill, and Charles K. Meshul
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Substantia nigra ,Striatum ,Motor Activity ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Parkinsonian Disorders ,Dopamine ,Internal medicine ,medicine ,Animals ,Immunologic Factors ,Neurotoxin ,Tyrosine hydroxylase ,Pars compacta ,business.industry ,Brain-Derived Neurotrophic Factor ,General Neuroscience ,MPTP ,Calcium-Binding Proteins ,Microfilament Proteins ,Glatiramer Acetate ,medicine.disease ,nervous system diseases ,Substantia Nigra ,Neuroprotective Agents ,030104 developmental biology ,Endocrinology ,nervous system ,chemistry ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disease and there are no effective treatments that either slow or reverse the degeneration of the dopamine (DA) pathway. Using a 4-week progressive MPTP (1-methyl-1,2,3,6-tetrahydropyridine) neurotoxin model of PD, which is characterized by neuroinflammation, loss of nigrostriatal DA, and motor dysfunction, as seen in patients with PD, we tested whether post-MPTP treatment with glatiramer acetate (GA), an immunomodulatory drug, could reverse these changes. GA restored the grip dysfunction and gait abnormalities that were evident in the MPTP treated group. The reversal of the motor dysfunction was attributable to the substantial recovery in tyrosine hydroxylase (TH) protein expression in the striatum. Within the substantia nigra pars compacta, surface cell count analysis showed a slight increase in TH+ cells following GA treatment in the MPTP group, which was not statistically different from the vehicle (VEH) group. This was associated with the recovery of BDNF (brain derived neurotrophic factor) protein levels and a reduction in the microglial marker, IBA1, protein expression within the midbrain. Alpha synuclein (syn-1) levels within the midbrain and striatum were decreased following MPTP, while GA facilitated recovery to VEH levels in the striatum in the MPTP group. Although DA tissue analysis revealed no significant increase in striatal DA or 3,4-Dihydroxyphenylacetic acid levels (DOPAC) in the MPTP group treated with GA, DA turnover (DOPAC/DA) recovered back to VEH levels following GA treatment. GA treatment effectively reversed clinical (motor dysfunction) and pathology (TH, IBA1, BDNF expression) of PD in a murine model.
- Published
- 2019
20. Glutamate-Glutamine Transfer and Chronic Stress-Induced Sex Differences in Cocaine Responses
- Author
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Malcolm Edwards, Christopher Davis, Alicia Wilson, Virginie Rappeneau, Cynthia Moore, Havisha Munjal, Collin Reynolds, Tonie Farris, Akiko Shimamoto, and Charles K. Meshul
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Male ,0301 basic medicine ,medicine.medical_specialty ,Amino Acid Transport System A ,Amino Acid Transport Systems ,Prefrontal Cortex ,Nucleus accumbens ,Nucleus Accumbens ,Social defeat ,03 medical and health sciences ,Glutamatergic ,0302 clinical medicine ,Cocaine ,Internal medicine ,medicine ,Animals ,Rats, Long-Evans ,Chronic stress ,Social Behavior ,Prefrontal cortex ,Depressive Disorder, Major ,Sex Characteristics ,Behavior, Animal ,Glutaminase ,Chemistry ,General Neuroscience ,Glutamate receptor ,Mitochondria ,Glutamine ,030104 developmental biology ,Endocrinology ,Excitatory Amino Acid Transporter 2 ,Synapses ,Female ,Locomotion ,Stress, Psychological ,030217 neurology & neurosurgery - Abstract
Substance use disorders (SUD) often co-occur with other mental disorders such as major depression (MD). Our previous findings revealed sex-dependent changes in extracellular levels of glutamate (Glu) and glutamine (Gln) in the nucleus accumbens (NAc) in Long–Evans rats that were exposed to 21 days of chronic social defeat stress (CSDS), which models MD. The current study investigated the role of a Gln transporter called sodium-coupled neutral amino acid transporter subtype 1/2 (SNAT 1/2), phosphate-activated glutaminase (PAG), and astrocytic glutamate transporter-1 (GLT-1) on CSDS animals exposed to cocaine. Before cocaine exposure, CSDS males already showed decreased levels of SNAT 1/2 in the NAc and prefrontal cortex (PFC) compared to non-CSDS controls. The reduction in SNAT 1/2 levels was associated with an increase in Gln localization in the mitochondrial outer membrane in accumbal glutamatergic nerve terminals projecting from the PFC. CSDS females showed increased GLT-1 levels in the NAc and PFC compared to non-CSDS controls. Both acute and repeated cocaine exposure attenuated locomotor responses in CSDS males but increased those in CSDS females. Cocaine reduced SNAT 1/2 levels in the NAc but increased them in the PFC in CSDS males. Additionally, both PAG and GLT-1 levels were increased in the PFC in CSDS males. On the other hand, cocaine reduced SNAT 1/2 and GLT-1 levels in the NAc and PFC in CSDS females. Our results show that CSDS altered locomotor responses upon cocaine exposure in a sex-dependent manner that may be mediated by molecules associated with the Glu-Gln transfer.
- Published
- 2018
21. Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington’s Disease Mouse Striatum
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Maile C. Neel, Lexi Kopan, Cynthia Moore, Charles K. Meshul, Sylvia Y. Yeung, Sandra M. Holley, Gerhard Bauer, Jack C. Reidling, Michael Levine, Leslie M. Thompson, Edwin S. Monuki, Brian Fury, Carlos Cepeda, Dane P. Coleal‐Bergum, Alice Lau, and Iliana Orellana
- Subjects
Transplantation ,Huntingtin ,nervous system ,Huntington's disease ,Neurotrophic factors ,medicine ,Patch clamp ,Striatum ,Biology ,medicine.disease ,Neuroscience ,Neural stem cell ,Cortex (botany) - Abstract
Huntington’s disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.
- Published
- 2021
22. Neurogenesis is enhanced in young rats with genetic absence epilepsy: An immuno-electron microscopic study
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Serap Sirvanci, Onat Filiz, Charles K. Meshul, Ozlem Tugce Cilingir-Kaya, Cynthia Moore, and Duygu Gursoy
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Male ,Doublecortin Protein ,Neurogenesis ,Vesicular glutamate transporter 1 ,Hippocampus ,Doublecortin ,Hippocampal formation ,GABA ,medicine ,Animals ,Rats, Wistar ,Axon ,gamma-Aminobutyric Acid ,Neurons ,biology ,business.industry ,Dentate gyrus ,Immunoelectron Microscopy ,Immunohistochemistry ,Rats ,Microscopy, Electron ,medicine.anatomical_structure ,Epilepsy, Absence ,nervous system ,Synapses ,GAERS ,biology.protein ,GABAergic ,Surgery ,Neurology (clinical) ,Rats, Transgenic ,business ,Neuroscience ,VGLUT-1 - Abstract
Aim Neurogenesis is an age-related process that is closely associated with neurological disorders. In the present study, we aimed to investigate neurogenesis in both adult and 3-week-old genetic absence epilepsy rats from Strasbourg (GAERS) to determine if newly formed neurons within the dentate gyrus (DG) form synaptic contacts with GABAergic (gamma aminobutyric acid) and glutamatergic nerve terminals and compared to the control (non-GAERS) Wistar rats. Material and methods Brain tissue was processed for electron microscopic assessment. Thin sections from the hippocampal DG were double-labelled for anti-GABA or anti-VGLUT1 (vesicular glutamate transporter 1) and anti-doublecortin (DCX) antibodies using immunogold methodology and examined with the transmission electron microscope for morphological changes and to quantify the density of gold labeling. Results DCX immunoreactivity was demonstrated within axon terminals, dendrites and somata in all groups. DCX and GABA or VGLUT1 were found to be co-localized in the axon terminals in all groups. We observed that DCX-immunoreactive (-ir) profiles formed synaptic contacts with GABAergic and glutamatergic terminals. The percentage of DCX labeling in dendrites, compared to axons, and the percentage of DCX-ir terminal profiles forming asymmetrical synapses, compared to those forming symmetrical synapses, were increased in all groups compared to the control group. DCX immunoreactivity in the 21-day-old GAERS group was found to be increased compared to the Wistar group. Conclusion We conclude that newly born neurons are incorporated into the local hippocampal network in both the GAERS and the control Wistar rats. The results suggest that the neurogenesis taking place in the hippocampus may also be involved in the mechanism underlying absence seizures in GAERS.
- Published
- 2021
23. 025 Sleep Disruption on an Orbital Shaker alters Glutamate in Prairie Vole Prefrontal Cortex
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Niyati Puranik, Cynthia Moore, Randall Olson, Ryan Leriche, Charles K. Meshul, Christina Reynolds, Paul Marsh, Miranda M. Lim, Carolyn E. Jones, Hung Cao, Sung Sik Chu, Peyton Teutsch Wickham, and Alex Q. Chau
- Subjects
biology ,Physiology (medical) ,Glutamate receptor ,Neurology (clinical) ,Circadian rhythm ,Shaker ,Neurotransmission ,biology.organism_classification ,Prefrontal cortex ,Neuroscience ,Sleep in non-human animals ,Prairie vole ,Arousal - Abstract
Introduction Glutamate concentrations in the cortex fluctuate with the sleep wake cycle in both rodents and humans. Altered glutamatergic signaling, as well as the early life onset of sleep disturbances have been implicated in neurodevelopmental disorders such as autism spectrum disorder. In order to study how sleep modulates glutamate activity in brain regions relevant to social behavior and development, we disrupted sleep in the socially monogamous prairie vole (Microtus ochrogaster) rodent species and quantified markers of glutamate neurotransmission within the prefrontal cortex, an area of the brain responsible for advanced cognition and complex social behaviors. Methods Male and female prairie voles were sleep disrupted using an orbital shaker to deliver automated gentle cage agitation at continuous intervals. Sleep was measured using EEG/EMG signals and paired with real time glutamate concentrations in the prefrontal cortex using an amperometric glutamate biosensor. This same method of sleep disruption was applied early in development (postnatal days 14–21) and the long term effects on brain development were quantified by examining glutamatergic synapses in adulthood. Results Consistent with previous research in rats, glutamate concentration in the prefrontal cortex increased during periods of wake in the prairie vole. Sleep disruption using the orbital shaker method resulted in brief cortical arousals and reduced time in REM sleep. When applied during development, early life sleep disruption resulted in long-term changes in both pre- and post-synaptic components of glutamatergic synapses in the prairie vole prefrontal cortex including increased density of immature spines. Conclusion In the prairie vole rodent model, sleep disruption on an orbital shaker produces a sleep, behavioral, and neurological phenotype that mirrors aspects of autism spectrum disorder including altered features of excitatory neurotransmission within the prefrontal cortex. Studies using this method of sleep disruption combined with real time biosensors for excitatory neurotransmitters will enhance our understanding of modifiable risk factors, such as sleep, that contribute to the altered development of glutamatergic synapses in the brain and their relationship to social behavior. Support (if any) NSF #1926818, VA CDA #IK2 BX002712, Portland VA Research Foundation, NIH NHLBI 5T32HL083808-10, VA Merit Review #I01BX001643
- Published
- 2021
24. Differential ultrastructural alterations in the Vglut2 glutamatergic input to the substantia nigra pars compacta/pars reticulata following nigrostriatal dopamine loss in a progressive mouse model of Parkinson's disease
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Charles K. Meshul, Cynthia Moore, Jerry K. Bohlen, and Mo Xu
- Subjects
medicine.medical_specialty ,Dopamine ,Substantia nigra ,03 medical and health sciences ,chemistry.chemical_compound ,Glutamatergic ,Mice ,0302 clinical medicine ,Internal medicine ,Pars Reticulata ,medicine ,Animals ,Pars Compacta ,030304 developmental biology ,0303 health sciences ,Tyrosine hydroxylase ,Pars compacta ,General Neuroscience ,MPTP ,Glutamate receptor ,Parkinson Disease ,Substantia Nigra ,Subthalamic nucleus ,Endocrinology ,chemistry ,Pars reticulata ,030217 neurology & neurosurgery - Abstract
Loss of nigrostriatal dopamine (DA) in Parkinson's disease results in over-activation/bursting of the subthalamic nucleus (STN). The STN projects to the substantia nigra (SN) pars compacta (SNpc) and pars reticulata (SNpr). The vesicular glutamate transporter 2 (Vglut2) is localized within at least STN terminals synapsing within the SN, but it is not known if there are differential changes in the Vglut2+ input to the SNpc versus SNpr following DA loss. The goal/rationale of this current study was to determine whether there were differential changes in the density/levels of glutamate immuno-gold labeling within Vglut2+ nerve terminals synapsing in the SNpc/SNpr and in the proportion of Vglut2+ terminals contacting tyrosine hydroxylase (TH) positively(+) or negatively(-) labeled dendrites following DA loss. Within the SNpc, there was a significant increase (51.3%) in the density of nerve terminal glutamate immuno-gold labeling within Vglut2+ terminals synapsing on TH(-) dendrites following MPTP versus the vehicle (VEH) group. There was a significant decrease (16%) in the percentage of Vglut2+ terminals contacting TH(+) labeled dendrites in the MPTP- versus VEH-treated group within the SNpc. Within the SNpr, there was a significant decrease in the density of glutamate immuno-gold labeling in Vglut2+ terminals contacting TH(+) (71.5%) and TH(-) (55.5%) labeled dendrites, suggesting an increase in glutamate release. There was no change in the percentage of Vglut2+ terminals contacting TH(+) or TH(-) dendrites in the SNpr. We conclude that there is a differential effect following DA loss on the glutamate input from Vglut2+ terminals synapsing within the SNpr versus SNpc.
- Published
- 2020
25. ApoE isoform-specific differences in behavior and cognition associated with subchronic MPTP exposure
- Author
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Eileen Ruth S. Torres, Sydney Weber Boutros, Charles K. Meshul, and Jacob Raber
- Subjects
Gene isoform ,Apolipoprotein E ,Male ,medicine.medical_specialty ,Cognitive Neuroscience ,Apolipoprotein E4 ,Apolipoprotein E3 ,Spatial Learning ,Disease ,Water maze ,Motor Activity ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Neurotoxin ,Dementia ,Animals ,Behavior, Animal ,business.industry ,Parkinsonism ,MPTP ,Research ,MPTP Poisoning ,Recognition, Psychology ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Neuropsychology and Physiological Psychology ,Endocrinology ,chemistry ,Female ,business ,030217 neurology & neurosurgery - Abstract
Parkinson's disease (PD) is characterized clinically by progressive motor dysfunction; overt parkinsonism is often preceded by prodromal symptoms including disturbances in the sleep–wake cycle. Up to 80% of patients with PD also develop dementia. In humans, there are three major apolipoprotein E isoforms: E2, E3, and E4. Increased rate of dementia in PD may be associated with E4 isoform. To better understand prodromal changes associated with E4, we exposed young (3–5 mo) male and female mice expressing E3 or E4 via targeted replacement to a subchronic dosage of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We hypothesized that E4 mice would be more susceptible to MPTP-related behavioral and cognitive changes. MPTP-treated E4 mice explored novel objects longer than genotype-matched saline-treated mice. In contrast, saline-treated E3 mice preferentially explored the novel object whereas MPTP-treated E3 mice did not and showed impaired object recognition. MPTP treatment altered swim speed of E4, but not E3, mice in the water maze compared to controls. Thus, E4 carriage may influence the preclinical symptoms associated with PD. Increased efforts are warranted to study early time points in this disease model.
- Published
- 2020
26. Exercise in an animal model of Parkinson’s disease: Motor recovery but not restoration of the nigrostriatal pathway
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L. Pflibsen, Cynthia Moore, Michelle D Sconce, K. Kim, Madeline J Churchill, and Charles K. Meshul
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Nigrostriatal pathway ,Cell Count ,Substantia nigra ,Striatum ,Motor Activity ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Parkinsonian Disorders ,Dopamine ,Physical Conditioning, Animal ,Internal medicine ,Neural Pathways ,medicine ,Animals ,Dopamine transporter ,Dopamine Plasma Membrane Transport Proteins ,biology ,Pars compacta ,Dopaminergic Neurons ,General Neuroscience ,MPTP ,Calcium-Binding Proteins ,Microfilament Proteins ,Parkinson Disease ,Recovery of Function ,medicine.disease ,Corpus Striatum ,Mice, Inbred C57BL ,Substantia Nigra ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Excitatory Amino Acid Transporter 2 ,nervous system ,chemistry ,biology.protein ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Many clinical studies have reported on the benefits of exercise therapy in patients with Parkinson's disease (PD). Exercise cannot stop the progression of PD or facilitate the recovery of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) (Bega et al., 2014). To tease apart this paradox, we utilized a progressive MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine) mouse model in which we initiated 4 weeks of treadmill exercise after the completion of toxin administration (i.e., restoration). We found in our MPTP/exercise (MPTP + EX) group several measures of gait function that recovered compared to the MPTP only group. Although there was a small recovery of tyrosine hydroxylase (TH) positive DA neurons in the SNpc and terminals in the striatum, this increase was not statistically significant. These small changes in TH could not explain the improvement of motor function. The MPTP group had a significant 170% increase in the glycosylated/non-glycosylated dopamine transporter (DAT) and a 200% increase in microglial marker, IBA-1, in the striatum. The MPTP + EX group showed a nearly full recovery of these markers back to the vehicle levels. There was an increase in GLT-1 levels in the striatum due to exercise, with no change in striatal BDNF protein expression. Our data suggest that motor recovery was not prompted by any significant restoration of DA neurons or terminals, but rather the recovery of DAT and dampening the inflammatory response. Although exercise does not promote recovery of nigrostriatal DA, it should be used in conjunction with pharmaceutical methods for controlling PD symptoms.
- Published
- 2017
27. Plastic changes at corticostriatal synapses predict improved motor function in a partial lesion model of Parkinson’s disease
- Author
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Charles K. Meshul, Lise Verbruggen, Eduard Bentea, Madeline J Churchill, Lauren Deneyer, Rebecca L. Hood, Ann Massie, Cynthia Moore, Faculty of Sciences and Bioengineering Sciences, Pharmaceutical and Pharmacological Sciences, and Faculty of Medicine and Pharmacy
- Subjects
Male ,0301 basic medicine ,Cerebral Cortex/drug effects ,Motor Activity/drug effects ,Parkinson Disease/pathology ,Substantia nigra ,Motor Activity ,Rotarod performance test ,03 medical and health sciences ,0302 clinical medicine ,Parkinsonian Disorders/chemically induced ,Parkinsonian Disorders ,Postsynaptic potential ,Dopamine ,Neural Pathways ,medicine ,Animals ,Pars Compacta/drug effects ,Pars Compacta ,Cerebral Cortex ,Synapses/drug effects ,Neuronal Plasticity ,Behavior, Animal ,Pars compacta ,General Neuroscience ,Neuronal Plasticity/drug effects ,Post-Synaptic Density ,Parkinson Disease ,Corpus Striatum ,Acetylcysteine ,Corpus Striatum/drug effects ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,nervous system ,Rotarod Performance Test ,Synapses ,Synaptic plasticity ,Acetylcysteine/administration & dosage ,Excitatory postsynaptic potential ,Post-Synaptic Density/drug effects ,Psychology ,Neural Pathways/drug effects ,Neuroscience ,Postsynaptic density ,030217 neurology & neurosurgery ,medicine.drug - Abstract
In Parkinson's disease, striatal dopamine depletion leads to plastic changes at excitatory corticostriatal and thalamostriatal synapses. The functional consequences of these responses on the expression of behavioral deficits are incompletely understood. In addition, most of the information on striatal synaptic plasticity has been obtained in models with severe striatal dopamine depletion, and less is known regarding changes during early stages of striatal denervation. Using a partial model of nigral cell loss based on intranigral injection of the proteasome inhibitor lactacystin, we demonstrate ultrastructural changes at corticostriatal synapses with a 15% increase in the length and 30% increase in the area of the postsynaptic densities at corticostriatal synapses 1 week following toxin administration. This increase was positively correlated with the performance of lactacystin-lesioned mice on the rotarod task, such that mice with a greater increase in the size of the postsynaptic density performed better on the rotarod task. We therefore propose that lengthening of the postsynaptic density at corticostriatal synapses acts as a compensatory mechanism to maintain motor function under conditions of partial dopamine depletion. The ultrastructure of thalamostriatal synapses remained unchanged following lactacystin administration. Our findings provide novel insights into the mechanisms of synaptic plasticity and behavioral compensation following partial loss of substantia nigra pars compacta neurons, such as those occurring during the early stages of Parkinson's disease.
- Published
- 2017
28. Demonstration of Doublecortin Protein, a Neurogenesis Marker, at the Electron Microscopic Level
- Author
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Charles K. Meshul, Cynthia Moore, Özlem Tuğçe Çilingir Kaya, and Serap Sirvanci
- Subjects
Physics ,Health Care Sciences and Services ,Nörogenez,doublecortin,gömme öncesi mikrodalga tekniği,immün-elektron mikroskopi ,Neurogenesis,doublecortin,pre-embedding microwave technique,immunoelectron microscopy ,General Medicine ,Sağlık Bilimleri ve Hizmetleri ,Molecular biology - Abstract
Objective: Demonstration of newly born neurons in adult brains is an important issue in terms of elucidating neurogenesis. In our study, we aimed to develop an appropriate pre-embedding microwave labeling method for the newly born neuronal marker doublecortin (DCX) protein in the hippocampal dentate gyrus (DG) region. Methods: Brains were obtained from 10-week-old C57BJ/6J male mice by perfusion fixation. Vibratome sections from brain tissues were labeled with an anti-DCX antibody using a pre-embedding microwave method. Sections stained with 3.3'-diaminobenzidine (DAB) were prepared for electron microscopic (EM) analyses using a microwave. After embedding in Epon, thin sections were obtained, observed under an electron microscope, and photographed for morphological assessments. Results: DCX labeling performed using the pre-embedding microwave method was specifically demonstrated at both light and electron microscopic levels. DCX-positive cells were localized at the subgranular zone and granular layer. Electron microscopic observations showed that DCX immunoreactivity was positive at the axons, dendrites, and somata. Conclusion: We demonstrated that the existence of DCX can be determined using the pre-embedding microwave labeling as an immunoelectron method in the DG region. Our study provides a basis for further studies on neurogenesis aiming to show DCX-immunoreactive cells using the pre-embedding DAB labeling method at the electron microscopic level., Amaç: Yetişkin beyninde yeni oluşan nöronların gösterilmesi nörogenez sürecinin aydınlatılması açısından önem taşımaktadır. Çalışmamızda hipokampusun dentat girus (DG) bölgesinde, yeni oluşan nöron belirteci olan doublecortin (DCX) proteini için uygun gömme öncesi mikrodalga işaretleme metodu oluşturmayı amaçladık. Yöntemler: 10 haftalık C57BJ/6J erkek farelerden perfüzyon fiksasyonu ile beyin dokuları elde edildi. Vibratom ile beyin dokularından alınan kesitler, gömme öncesi mikrodalga yöntemi ile anti-DCX antikoru ile işaretlendi. 3,3'-diaminobenzidin (DAB) ile boyanan dokular, mikrodalga yardımı ile elektron mikroskopik analizler için hazırlandı. Epon bloklar üzerindeki dokulardan ince kesitler alınarak elektron mikroskobunda incelendi ve morfolojik analiz için fotoğraflandı. Bulgular: Mikrodalga yöntemi kullanılarak yapılan gömme öncesi DCX işaretlemesi hem ışık hem de elektron mikroskopik (EM) düzeyde spesifik olarak gösterildi. DCX pozitif hücrelerin subgranüler zon (SGZ) ve granüler tabakada yerleşim gösterdikleri izlendi. Elektron mikroskopik incelemelerde DCX immünreaktivitesinin akson, dendrit ve hücre gövdeleri üzerinde pozitif olduğu gözlendi. Sonuç: Çalışmamızda, mikrodalga kullanılarak yapılan gömme öncesi immün-elektron yöntemi ile DG bölgesinde DCX varlığının belirlenebildiğini gösterdik. Çalışmamız DCX immünreaktif hücreleri, gömme öncesi DAB işaretlemesi ile elektron mikroskopik düzeyde göstererek, nörogenez sürecinin araştırılacağı ileri çalışmalar için temel oluşturmaktadır.
- Published
- 2017
29. Effects of sleep disruption on stress, nigrostriatal markers, and behavior in a chronic/progressive MPTP male mouse model of parkinsonism
- Author
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Cynthia Moore, Michelle A. Nipper, Deborah A. Finn, Mo Xu, Charles K. Meshul, Jerry K. Bohlen, Carolyn E. Jones, and Miranda M. Lim
- Subjects
Male ,0301 basic medicine ,animal diseases ,Nigrostriatal pathway ,Striatum ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Single-Blind Method ,biology ,MPTP ,Parkinsonism ,Substantia Nigra ,Sleep Disorders, Intrinsic ,medicine.anatomical_structure ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,cardiovascular system ,medicine.drug ,medicine.medical_specialty ,Tyrosine 3-Monooxygenase ,Nerve Tissue Proteins ,Substantia nigra ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Parkinsonian Disorders ,Stress, Physiological ,Dopamine ,Internal medicine ,medicine ,Animals ,cardiovascular diseases ,Oxidopamine ,Gait Disorders, Neurologic ,Dopamine transporter ,Dopamine Plasma Membrane Transport Proteins ,Pars compacta ,business.industry ,medicine.disease ,Corpus Striatum ,nervous system diseases ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,nervous system ,chemistry ,Vesicular Monoamine Transport Proteins ,biology.protein ,Corticosterone ,business ,030217 neurology & neurosurgery - Abstract
Sleep complaints are an early clinical symptom of neurodegenerative disorders. Patients with Parkinson's disease (PD) experience sleep disruption (SD). The objective of this study was to determine if preexisting, chronic SD leads to a greater loss of tyrosine hydroxylase (TH) within the striatum and the substantia nigra following chronic/progressive exposure with the neurotoxin, 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice underwent chronic SD for 4 weeks, then injected with vehicle (VEH) or increasing doses of MPTP for 4 weeks. There was a significant decrease in the plasma corticosterone levels in the MPTP group, an increase in the SD group, and a return to the VEH levels in the SD+MPTP group. Protein expression levels for TH in the striatum (terminals) and substantia nigra pars compacta (dopamine [DA] cell counts) revealed up to a 78% and 38% decrease, respectively, in the MPTP and SD+MPTP groups compared to their relevant VEH and SD groups. DA transporter protein expression increased in the striatum in the MPTP versus VEH group and in the SN/midbrain between the SD+MPTP and the VEH group. There was a main effect of MPTP on various gait measures (e.g., braking) relative to the SD or VEH groups. In the SD+MPTP group, there were no differences compared to the VEH group. Thus, SD, prior to administration of MPTP, has effects on serum corticosterone and gait but more importantly does not potentiate greater loss of TH within the nigrostriatal pathway compared to the MPTP group, suggesting that in PD patients with SD, there is no exacerbation of the DA cell loss.
- Published
- 2019
30. The cystine/glutamate antiporter system xc- as modulator of corticostriatal neurotransmission
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Hideyo Sato, Adam J. Funk, Lise Verbruggen, Eduard Bentea, Madeline J Churchill, Laura De Pauw, Agnès Villers, Charles K. Meshul, Robert E. McCullumsmith, Ann Massie, Laurence Ris, Erica A K DePasquale, Cynthia Moore, Sinead M. O’Donovan, Olaya Lara, Faculty of Medicine and Pharmacy, and Pharmaceutical and Pharmacological Sciences
- Subjects
chemistry.chemical_compound ,Chemistry ,General Neuroscience ,Antiporter ,Glutamate receptor ,Cystine ,Neurotransmission ,Cell biology - Abstract
The cystine/glutamate antiporter system xc-, with xCT as specific subunit, exchanges intracellular glutamate for extracellular cystine. It is highly expressed in the central nervous system, mainly on astrocytes, and has been shown to be the major source of extracellular glutamate in various regions of the brain, such as the striatum and hippocampus. This extrasynaptically released glutamate can affect synaptic neurotransmission. As the physiological function of system xc- in the central nervous system remains poorly understood, we studied how system xc- regulates transmission at corticostriatal synapses, one of the two major types of striatal excitatory synapses. Electrophysiological recordings identified a significant decrease in the amplitude of striatal field excitatory postsynaptic potentials in mice genetically lacking xCT (xCT-/- mice) following stimulation of corticostriatal fibers. Further, using electron microscopy, we observed depletion of glutamate immunogold labeling from corticostriatal terminalsand their corresponding dendritic spines in xCT-/- mice. Genetic deletion of xCT did not, however, affect the morphology of corticostriatal synapses, the density of cortical innervation or the density of dendritic spines in the striatum. Proteomic analysis revealed decreased expression of a wide range of proteins involved in regulating presynaptic neurotransmitter release in the striatum of xCT-/- mice, including synaptophysin, VGLUT1, and members of the synapsin, septin, and syntaxin families. In addition, kinome profiling identified changes in striatal serine/threonine kinase activity, highlighting ERK signaling as a possible node of kinase dysregulation in xCT-/- mice. Finally, we evaluated the effect of the disturbed corticostriatal communication on the behavioral phenotype of the xCT-/- mice. In the marble burying test, a paradigm sensitive to changes in corticostriatal function, we measured a significant increase in repetitive digging behavior in xCT-/- mice. Whereas spontaneous grooming behavior was not affected by genetic deletion of xCT, we have preliminary findings from the reciprocal interaction and three-chamber test, suggesting aberrant social behavior. Together, our results identify system xc- as a modulator of corticostriatal synaptic transmission that may be relevant to neuropsychiatric disorders characterized by corticostriatal dysfunction and repetitive behavior, such as obsessive-compulsive behavior and autism.
- Published
- 2019
31. Cognitive and anxiety-like impairments accompanied by serotonergic ultrastructural and immunohistochemical alterations in early stages of parkinsonism
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Alessandra Mussi Ribeiro, José R. Santos, Cynthia Moore, Auderlan M. Gois, Lívia C.R.F. Lins, Pollyana Caldeira Leal, Regina H. Silva, José M.M. Bispo, Charles K. Meshul, Murilo Marchioro, and Marina F. Souza
- Subjects
0301 basic medicine ,Male ,Serotonin ,Parkinson's disease ,Reserpine ,Tyrosine 3-Monooxygenase ,Dopamine ,Prefrontal Cortex ,Anxiety ,Motor Activity ,Serotonergic ,03 medical and health sciences ,0302 clinical medicine ,Cognition ,Parkinsonian Disorders ,Medicine ,Animals ,Rats, Wistar ,Prefrontal cortex ,CA1 Region, Hippocampal ,Tyrosine hydroxylase ,business.industry ,General Neuroscience ,Parkinsonism ,Dopaminergic ,Brain ,Parkinson Disease ,medicine.disease ,Immunohistochemistry ,Corpus Striatum ,Rats ,Disease Models, Animal ,030104 developmental biology ,Memory, Short-Term ,nervous system ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug ,Serotonergic Neurons - Abstract
Parkinson’s disease (PD) is mostly known as a dopamine deficiency syndrome due the structural and functional changes in striatal projection neurons. However, studies have considered this pathology as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the morphological and immunohistochemical changes associated with behavioral and cognitive alterations in a model of parkinsonism induced by low dose of reserpine. Animals showed anxiety–like behavior and deficits in short-term recognition memory. Besides, Tyrosine Hydroxylase (TH) immunoreactive cells decreased in reserpine (RES) group in CA1 and serotonin (5-HT) immunoreactive cells decreased in RES group in CA1, CA3 and medial prefrontal cortex (mPFC). Moreover, an increase in the area (μm2) of 5 H T labeled ultrastructure (axon terminal) was observed in RES group only in CA1 and mPFC. The evidence of alterations in 5-HT immunoreactive in the premotor phase of model of parkinsonism highlights the importance of looking beyond the nigrostriatal system to elucidate the underling mechanisms and deficits in other neurotransmitters systems. This provides vital information regarding novel interventions for the management of non-motor symptoms. Additionally, the low-dose reserpine treatment has an early effect on axonal ultrastructure. As the axonopathy in PD has been increasingly recognized, the focus on axonal neurobiology is noteworthy for both neuroprotective and restorative therapeutics, and the progressive reserpine rat model can be a useful tool in this search.
- Published
- 2018
32. The key role of T cells in Parkinson's disease pathogenesis and therapy
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Charles K. Meshul, Dennis Bourdette, Joseph F. Quinn, and Jill K. Baird
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0301 basic medicine ,Parkinson's disease ,T-Lymphocytes ,Disease ,Neuroprotection ,03 medical and health sciences ,0302 clinical medicine ,Dopamine ,Medicine ,Animals ,Humans ,Immunologic Factors ,Glatiramer acetate ,Neuroinflammation ,Inflammation ,business.industry ,Multiple sclerosis ,Dopaminergic ,Parkinson Disease ,medicine.disease ,030104 developmental biology ,Neurology ,Immunology ,Disease Progression ,Neurology (clinical) ,Geriatrics and Gerontology ,business ,030217 neurology & neurosurgery ,Biomarkers ,medicine.drug - Abstract
This review focuses on the role of T lymphocytes in the pathogenesis of Parkinson's disease and highlights evidence for modulation of the T cell response as an effective neuroprotective strategy. In preclinical models of Parkinson's disease, modulation of the T cell response results in neuroprotection. Peripheral markers of T cell response show changes in Parkinson's patients relative to controls that have potential application as diagnostic and therapeutic biomarkers. The article also discusses the important immunomodulatory effects of dopamine which may confound study of T cells in patients on dopaminergic therapies, and highlights glatiramer acetate, an FDA-approved therapy for multiple sclerosis that works through modulating the T cell response, as a promising target for translation.
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- 2018
33. Dietary therapy restores glutamatergic input to orexin/hypocretin neurons after traumatic brain injury in mice
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Miranda M. Lim, Madeline J Churchill, Charles K. Meshul, Samuel E De Luche, Jonathan E. Elliott, Akiva S. Cohen, and Cynthia Moore
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0301 basic medicine ,Male ,medicine.medical_specialty ,Hypothalamus ,Presynaptic Terminals ,Basic Science of Sleep and Circadian Rhythms ,Glutamic Acid ,Inhibitory postsynaptic potential ,gamma-Aminobutyric acid ,03 medical and health sciences ,Glutamatergic ,Mice ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,Brain Injuries, Traumatic ,medicine ,Premovement neuronal activity ,Animals ,Neurons ,Orexins ,Chemistry ,Glutamate receptor ,Orexin ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,nervous system ,Hypothalamic Area, Lateral ,Excitatory postsynaptic potential ,Neurology (clinical) ,Neuron ,Sleep ,030217 neurology & neurosurgery ,medicine.drug ,Diet Therapy - Abstract
Study objectives In previous work, dietary branched-chain amino acid (BCAA) supplementation, precursors to de novo glutamate and γ-aminobutyric acid (GABA) synthesis, restored impaired sleep-wake regulation and orexin neuronal activity following traumatic brain injury (TBI) in mice. TBI was speculated to reduce orexin neuronal activity through decreased regional excitatory (glutamate) and/or increased inhibitory (GABA) input. Therefore, we hypothesized that TBI would decrease synaptic glutamate and/or increase synaptic GABA in nerve terminals contacting orexin neurons, and BCAA supplementation would restore TBI-induced changes in synaptic glutamate and/or GABA. Methods Brain tissue was processed for orexin pre-embed diaminobenzidine labeling and glutamate or GABA postembed immunogold labeling. The density of glutamate and GABA immunogold within presynaptic nerve terminals contacting orexin-positive lateral hypothalamic neurons was quantified using electron microscopy in three groups of mice (n = 8 per group): Sham/noninjured controls, TBI without BCAA supplementation, and TBI with BCAA supplementation (given for 5 days, 48 hr post-TBI). Glutamate and GABA were also quantified within the cortical penumbral region (layer VIb) adjacent to the TBI lesion. Results In the hypothalamus and cortex, TBI decreased relative glutamate density in presynaptic terminals making axodendritic contacts. However, BCAA supplementation only restored relative glutamate density within presynaptic terminals contacting orexin-positive hypothalamic neurons. BCAA supplementation did not change relative glutamate density in presynaptic terminals making axosomatic contacts, or relative GABA density in presynaptic terminals making axosomatic or axodendritic contacts, within either the hypothalamus or cortex. Conclusions These results suggest TBI compromises orexin neuron function via decreased glutamate density and highlight BCAA supplementation as a potential therapy to restore glutamate density to orexin neurons.
- Published
- 2018
34. Human Neural Stem Cell Transplantation Rescues Functional Deficits in R6/2 and Q140 Huntington's Disease Mice
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Carlos Cepeda, Alvin R. King, Joshua Barry, Dane P. Coleal‐Bergum, Jack C. Reidling, Gerhard Bauer, Alice Lau, Andrew H. Tran, Talia Kamdjou, Sandra M. Holley, Sylvia Y. Yeung, Brian Fury, Asa Hatami, Chunni Zhu, Charles K. Meshul, Joseph Ochaba, Delaram Salamati, Mathew Blurton-Jones, Frank M. LaFerla, Aroa Relano-Gines, Marie-Françoise Chesselet, Nicholas R. Franich, Cynthia Moore, Michael S. Levine, Joan S. Steffan, and Leslie M. Thompson
- Subjects
0301 basic medicine ,Huntingtin ,Human Embryonic Stem Cells ,Striatum ,Motor Activity ,Biology ,Biochemistry ,Article ,Cell Line ,Mice ,03 medical and health sciences ,neural stem cell ,Cognition ,0302 clinical medicine ,Neural Stem Cells ,Huntington's disease ,Neurotrophic factors ,Genetics ,medicine ,Animals ,Humans ,lcsh:QH301-705.5 ,lcsh:R5-920 ,R6/2 mice ,Recovery of Function ,Cell Biology ,embryonic stem cells ,medicine.disease ,Embryonic stem cell ,Neural stem cell ,Q140 mice ,Transplantation ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,lcsh:Biology (General) ,Heterografts ,Stem cell ,lcsh:Medicine (General) ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology ,transplantation - Abstract
Summary Huntington's disease (HD) is an inherited neurodegenerative disorder with no disease-modifying treatment. Expansion of the glutamine-encoding repeat in the Huntingtin (HTT) gene causes broad effects that are a challenge for single treatment strategies. Strategies based on human stem cells offer a promising option. We evaluated efficacy of transplanting a good manufacturing practice (GMP)-grade human embryonic stem cell-derived neural stem cell (hNSC) line into striatum of HD modeled mice. In HD fragment model R6/2 mice, transplants improve motor deficits, rescue synaptic alterations, and are contacted by nerve terminals from mouse cells. Furthermore, implanted hNSCs are electrophysiologically active. hNSCs also improved motor and late-stage cognitive impairment in a second HD model, Q140 knockin mice. Disease-modifying activity is suggested by the reduction of aberrant accumulation of mutant HTT protein and expression of brain-derived neurotrophic factor (BDNF) in both models. These findings hold promise for future development of stem cell-based therapies., Highlights • hNSCs implanted in R6/2 HD mice improved motor and electrophysiological deficits • hNSCs are electrophysiologically active and are contacted by host nerve terminals • hNSCs improved motor and late-stage cognitive impairment in Q140 knockin mice • hNSCs reduced aberrant accumulation of mHTT protein and increased BDNF production, Human GMP-grade neural stem cell transplantation rescues behavioral deficits and electrophysiological alterations in Huntington's disease mice, and rescue is associated with reduced accumulation of mutant Huntingtin protein.
- Published
- 2018
35. Differential electrophysiological and morphological alterations of thalamostriatal and corticostriatal projections in the R6/2 mouse model of Huntington's disease
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Carlos Cepeda, Cynthia Moore, Anna Parievsky, Talia Kamdjou, Charles K. Meshul, and Michael Levine
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0301 basic medicine ,Male ,Huntington's Disease ,Patch-Clamp Techniques ,Excitotoxicity ,Striatum ,Neurodegenerative ,medicine.disease_cause ,Transgenic ,Tissue Culture Techniques ,Mice ,0302 clinical medicine ,Thalamus ,Postsynaptic potential ,Neural Pathways ,Receptors ,AMPA ,Glutamate reuptake ,Cerebral Cortex ,Neurons ,Microscopy ,Glutamate receptor ,Huntington's disease ,Immunohistochemistry ,Huntington Disease ,Neurology ,Excitatory postsynaptic potential ,NMDA receptor ,Female ,N-Methyl-D-Aspartate ,Clinical Sciences ,Glutamic Acid ,Mice, Transgenic ,AMPA receptor ,Biology ,Receptors, N-Methyl-D-Aspartate ,Electron ,Article ,lcsh:RC321-571 ,03 medical and health sciences ,Rare Diseases ,Medium-sized spiny neurons ,medicine ,Electron microscopy ,Genetics ,Animals ,Receptors, AMPA ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neurology & Neurosurgery ,Animal ,Neurosciences ,R6/2 ,Corpus Striatum ,Brain Disorders ,Optogenetics ,Disease Models, Animal ,Microscopy, Electron ,030104 developmental biology ,Synapses ,Disease Models ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington's disease (HD) is a fatal genetic disorder characterized by cell death of medium-sized spiny neurons (MSNs) in the striatum, traditionally attributed to excessive glutamate inputs and/or receptor sensitivity. While changes in corticostriatal projections have typically been studied in mouse models of HD, morphological and functional alterations in thalamostriatal projections have received less attention. In this study, an adeno-associated virus expressing channelrhodopsin-2 under the calcium/calmodulin-dependent protein kinase IIα promoter was injected into the sensorimotor cortex or the thalamic centromedian-parafascicular nuclear complex in the R6/2 mouse model of HD, to permit selective activation of corticostriatal or thalamostriatal projections, respectively. In symptomatic R6/2 mice, peak amplitudes and areas of corticostriatal glutamate AMPA and NMDA receptor-mediated responses were reduced. In contrast, although peak amplitudes of AMPA and NMDA receptor-mediated thalamostriatal responses also were reduced, the areas remained unchanged due to an increase in response decay times. Blockade of glutamate reuptake further increased response areas and slowed rise and decay times of NMDA responses. These effects appeared more pronounced at thalamostriatal synapses of R6/2 mice, suggesting increased activation of extrasynaptic NMDA receptors. In addition, the probability of glutamate release was higher at thalamostriatal than corticostriatal synapses, particularly in R6/2 mice. Morphological studies indicated that the density of all excitatory synaptic contacts onto MSNs was reduced, which matches the basic electrophysiological findings of reduced amplitudes. There was a consistent reduction in the area of spines but little change in presynaptic terminal size, indicating that the postsynaptic spine may be more significantly affected than presynaptic terminals. These results highlight the significant and differential contribution of the thalamostriatal projection to glutamate excitotoxicity in HD.
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- 2017
36. Executive function deficits and glutamatergic protein alterations in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease
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Charles K. Meshul, Katherine A. Stang, Rebecca L. Hood, Vanessa B. Wilson, Lacey Pflibsen, Michelle D Sconce, and Suzanne H. Mitchell
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Parkinson's disease ,biology ,MPTP ,Dopaminergic ,Striatum ,medicine.disease ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Glutamatergic ,nervous system ,chemistry ,Dopamine ,medicine ,biology.protein ,MPTP Poisoning ,Psychology ,Neuroscience ,medicine.drug ,Dopamine transporter - Abstract
Changes in executive function are at the root of most cognitive problems associated with Parkinson's disease. Because dopaminergic treatment does not necessarily alleviate deficits in executive function, it has been hypothesized that dysfunction of neurotransmitters/systems other than dopamine (DA) may be associated with this decrease in cognitive function. We have reported decreases in motor function and dopaminergic/glutamatergic biomarkers in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Parkinson's mouse model. Assessment of executive function and dopaminergic/glutamatergic biomarkers within the limbic circuit has not previously been explored in our model. Our results show progressive behavioral decline in a cued response task (a rodent model for frontal cortex cognitive function) with increasing weekly doses of MPTP. Although within the dorsolateral (DL) striatum mice that had been given MPTP showed a 63% and 83% loss of tyrosine hydroxylase and dopamine transporter expression, respectively, there were no changes in the nucleus accumbens or medial prefrontal cortex (mPFC). Furthermore, dopamine-1 receptor and vesicular glutamate transporter (VGLUT)-1 expression increased in the mPFC following DA loss. There were significant MPTP-induced decreases and increases in VGLUT-1 and VGLUT-2 expression, respectively, within the DL striatum. We propose that the behavioral decline following MPTP treatment may be associated with a change not only in cortical-cortical (VGLUT-1) glutamate function but also in striatal DA and glutamate (VGLUT-1/VGLUT-2) input.
- Published
- 2015
37. Intervention with 7,8-dihydroxyflavone blocks further striatal terminal loss and restores motor deficits in a progressive mouse model of Parkinson’s disease
- Author
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Michelle D Sconce, Cynthia Moore, Charles K. Meshul, and Madeline J Churchill
- Subjects
Male ,medicine.medical_specialty ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Substantia nigra ,Striatum ,Tropomyosin receptor kinase B ,Motor Activity ,7,8-Dihydroxyflavone ,Antiparkinson Agents ,Random Allocation ,chemistry.chemical_compound ,Internal medicine ,Forelimb ,Animals ,Receptor, trkB ,Medicine ,Phosphorylation ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Tyrosine hydroxylase ,business.industry ,General Neuroscience ,MPTP ,Calcium-Binding Proteins ,Intracellular Signaling Peptides and Proteins ,MPTP Poisoning ,Flavones ,medicine.disease ,Corpus Striatum ,Mice, Inbred C57BL ,Substantia Nigra ,Endocrinology ,nervous system ,chemistry ,Stathmin ,business ,Neuroscience - Abstract
Parkinson's disease (PD) is a progressive neurological disorder and current therapies help alleviate symptoms, but are not disease modifying. In the flavonoid class of compounds, 7,8-dihydroxyflavone (7,8-DHF) has been reported to elicit tyrosine kinase receptor B (TrkB) dimerization and autophosphorylation that further stimulates signaling cascades to promote cell survival/growth, differentiation, and plasticity. In this study we investigated if 7,8-DHF could prevent further loss of dopaminergic cells and terminals if introduced at the midpoint (i.e. intervention) of our progressive mouse model of PD. In our model, 1-methyl-4phenyl-1,2,3,6-tetrahyrdopyridine (MPTP) is administered with increased doses each week (8, 16, 24, 32-kg/mg) over a 4-week period. We found that despite 4 weeks of MPTP treatment, animals administered 7,8-DHF starting at the 2-week time period maintained 54% of the tyrosine hydroxylase (TH) levels within the dorsolateral (DL) striatum compared to the vehicle group, which was comparable to animals treated with MPTP for 2 weeks and was significantly greater compared to animals treated with MPTP for the full 4 weeks. Animals treated with MPTP and 7,8-DHF also demonstrated increased levels of, a sprouting-associated protein, superior cervical ganglion-10 (SCG10), phosphorylated TrkB (pTrkB), and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) within the DL striatum and substantia nigra (SN) compared to the 4-week MPTP-treated animals. In addition, motor deficits seen in the 2- and 4-week MPTP-treated animals were restored following administration of 7,8-DHF. We are reporting here for the first time that intervention with 7,8-DHF blocks further loss of dopaminergic terminals and restores motor deficits in our progressive MPTP mouse model. Our data suggest that 7,8-DHF has the potential to be a translational therapy in PD.
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- 2015
38. MPTP-induced parkinsonism in mice alters striatal and nigral xCT expression but is unaffected by the genetic loss of xCT
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Charles K. Meshul, Madeline J Churchill, Eduard-Mihai Bentea, Ann Massie, Hideyo Sato, Joeri Van Liefferinge, Michelle D Sconce, Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, and Neuro-Aging & Viro-Immunotherapy
- Subjects
Male ,medicine.medical_specialty ,Amino Acid Transport System y+ ,Tyrosine 3-Monooxygenase ,Dopamine ,animal diseases ,Excitotoxicity ,Substantia nigra ,Striatum ,medicine.disease_cause ,chemistry.chemical_compound ,Parkinsonian Disorders ,Internal medicine ,Forelimb ,medicine ,Animals ,Mice, Knockout ,Neurons ,Tyrosine hydroxylase ,General Neuroscience ,MPTP ,Neurodegeneration ,Dopaminergic ,Glutamate receptor ,medicine.disease ,Corpus Striatum ,nervous system diseases ,Substantia Nigra ,Endocrinology ,nervous system ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,3,4-Dihydroxyphenylacetic Acid ,Neuroscience - Abstract
Nigral cell loss in Parkinson’s disease (PD) is associated with disturbed glutathione (GSH) and glutamate levels, leading to oxidative stress and excitotoxicity, respectively. System xc- is a plasma membrane antiporter that couples cystine import (amino acid that can be further used for the synthesis of GSH) with glutamate export to the extracellular environment, and can thus affect both oxidative stress and glutamate excitotoxicity. In the current study, we evaluated the involvement of system xc- in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results indicate that the expression of xCT (the specific subunit of system xc-) undergoes region-specific changes in MPTP-treated mice, with increased expression in the striatum, and decreased expression in the substantia nigra. Furthermore, mice lacking xCT were equally sensitive to the neurotoxic effects of MPTP compared to wild-type (WT) mice, as they demonstrate similar decreases in striatal dopamine content, striatal tyrosine hydroxylase (TH) expression, nigral TH immunopositive neurons and forelimb grip strength, five weeks after commencing MPTP treatment. Altogether, our data indicate that progressive lesioning with MPTP induces striatal and nigral dysregulation of system xc-. However, loss of system xc- does not affect MPTP-induced nigral dopaminergic neurodegeneration and motor impairment in mice.
- Published
- 2015
39. [P2–144]: EXPLORING THE EFFECT OF CENTELLA ASIATICA ON MITOCHONDRIAL BIOGENESIS IN THE MOUSE BRAIN
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Charles Murchison, Cynthia Moore, Maya Caruso, Charles K. Meshul, Nora E. Gray, Joseph F. Quinn, Amala Soumyanath, Donald G. Matthews, and Chris Harris
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Psychiatry and Mental health ,Cellular and Molecular Neuroscience ,Centella ,Developmental Neuroscience ,Mitochondrial biogenesis ,Epidemiology ,Health Policy ,Neurology (clinical) ,Geriatrics and Gerontology ,Biology ,biology.organism_classification ,Cell biology - Published
- 2017
40. Pre- and postsynaptic changes at cortico-striatal synapses in xCT deficient mice
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Lise Verbruggen, Hideyo Sato, Eduard Bentea, Cynthia Moore, Madeline J Churchill, Charles K. Meshul, Laurence Ris, Rebecca L. Hood, Agnès Villers, Lauren Deneyer, Giulia Albertini, Ann Massie, Pharmaceutical and Pharmacological Sciences, Faculty of Medicine and Pharmacy, and Experimental Pharmacology
- Subjects
electron microscopy ,Chemistry ,xCT ,General Neuroscience ,Glutamate receptor ,glutamate ,Neurotransmission ,Synaptic Transmission ,Cell biology ,law.invention ,nervous system ,Postsynaptic potential ,law ,Deficient mouse ,corticostriatal pathway ,Electron microscope - Abstract
System xc- is a plasma membrane amino acid antiporter, of mainly glial origin, that couples the import of cystine with the export of glutamate. System xc- (specific subunit xCT) contributes substantially to ambient extracellular glutamate levels in various regions of the brain, including the striatum and hippocampus. Despite the fact that system xc- is highly expressed in the brain and is a proposed therapeutic target for various neurological disorders, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis and epilepsy, its function under physiological conditions in the central nervous system remains poorly understood. By acting as a source of glial extrasynaptic glutamate, system xc- might modulate synaptic transmission as a mechanism of neuro-glial communication. Previous electrophysiological findings indicate that system xc- delivered glutamate can inhibit excitatory synaptic neurotransmission in the cortico-accumbens pathway (Moran et al. J Neurosci. 2005; 25:6389-93) and at hippocampal CA3-CA1 synapses (Williams et al. J Neurosci. 2014; 34:16093-102). In order to gain further insight into the proposed function of system xc- as modulator of synaptic transmission, we carried out single section electron microscopy analyses of cortico-striatal excitatory synapses in adult xCT knockout (xCT-/-) and xCT wildtype (xCT+/+) mice. Our preliminary findings reveal depletion of glutamate immunogold labeling from presynaptic terminals of xCT-/- mice, an increase in the head diameter and area of spines contacted by asymmetric synapses, enlargement of the postsynaptic density and an increased occurrence of spinules, post-synaptic elements of high efficacy. These synaptic changes occurred in the absence of differences in the total density of cortico-striatal synapses or dendritic spines in the dorsolateral striatum of xCT-/- vs. xCT+/+ mice. Our results suggest the involvement of both presynaptic and postsynaptic forms of synaptic strength regulation via system xc-. Whether the structural changes we observedindicate a global increase in cortico-striatal transmission in xCT-/- mice, or conversely, represent forms of synaptic compensation, is being addressed by electrophysiological measures of excitatory post-synaptic currents in xCT-/- mice after cortical stimulation. Together, our findings shed new light on the re-organization of the glutamatergic system after genetic deletion of system xc-, and confirm the involvement of this antiporter in the control of synaptic strength in vivo.
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- 2017
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41. Presynaptic Alpha-Synuclein Aggregation in a Mouse Model of Parkinson's Disease
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Cynthia Moore, Charles K. Meshul, Kateri J. Spinelli, Jonathan Taylor, Valerie R. Osterberg, Madeline J Churchill, Eden Pollock, and Vivek K. Unni
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Male ,Presynaptic Terminals ,Mice, Transgenic ,Biology ,Synaptic vesicle ,Mice ,chemistry.chemical_compound ,In vivo ,Animals ,Humans ,Alpha-synuclein ,General Neuroscience ,Vesicle ,Glutamate receptor ,Fluorescence recovery after photobleaching ,Parkinson Disease ,Articles ,Synapsin ,nervous system diseases ,Disease Models, Animal ,nervous system ,Biochemistry ,chemistry ,alpha-Synuclein ,Biophysics ,Synuclein ,Female ,Fluorescence Recovery After Photobleaching - Abstract
Parkinson's disease and dementia with Lewy bodies are associated with abnormal neuronal aggregation of α-synuclein. However, the mechanisms of aggregation and their relationship to disease are poorly understood. We developed anin vivomultiphoton imaging paradigm to study α-synuclein aggregation in mouse cortex with subcellular resolution. We used a green fluorescent protein-tagged human α-synuclein mouse line that has moderate overexpression levels mimicking human disease. Fluorescence recovery after photobleaching (FRAP) of labeled protein demonstrated that somatic α-synuclein existed primarily in an unbound, soluble pool. In contrast, α-synuclein in presynaptic terminals was in at least three different pools: (1) as unbound, soluble protein; (2) bound to presynaptic vesicles; and (3) as microaggregates. Serial imaging of microaggregates over 1 week demonstrated a heterogeneous population with differing α-synuclein exchange rates. The microaggregate species were resistant to proteinase K, phosphorylated at serine-129, oxidized, and associated with a decrease in the presynaptic vesicle protein synapsin and glutamate immunogold labeling. Multiphoton FRAP provided the specific binding constants for α-synuclein's binding to synaptic vesicles and its effective diffusion coefficient in the soma and axon, setting the stage for future studies targeting synuclein modifications and their effects. Ourin vivoresults suggest that, under moderate overexpression conditions, α-synuclein aggregates are selectively found in presynaptic terminals.
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- 2014
42. Neurotransmitter CART as a New Therapeutic Candidate for Parkinson’s Disease
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Peizhong Mao, Charles K. Meshul, Philippe Thuillier, and P. Hemachandra Reddy
- Subjects
Cart ,antioxidant ,Parkinson's disease ,Pharmaceutical Science ,Review ,Disease ,Pharmacology ,Neuroprotection ,Cocaine and amphetamine regulated transcript ,cocaine- and amphetamine- regulated transcript ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dopamine ,Drug Discovery ,medicine ,oxidative stress ,Neurotransmitter ,030304 developmental biology ,0303 health sciences ,business.industry ,Dopaminergic ,medicine.disease ,3. Good health ,mitochondria ,nervous system ,chemistry ,Molecular Medicine ,neuroprotection ,dopamine ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Parkinson’s disease (PD) is one of the most common neurodegenerative diseases. To date, there is no effective treatment that halts its progression. Increasing evidence indicates that mitochondria play an important role in the development of PD. Hence mitochondria-targeted approaches or agents may have therapeutic promise for treatment of the disease. Neuropeptide CART (cocaine-amphetamine-regulated transcript), a hypothalamus and midbrain enriched neurotransmitter with an antioxidant property, can be found in mitochondria, which is the main source of reactive oxygen species. Systemic administration of CART has been found to ameliorate dopaminergic neuronal loss and improve motor functions in a mouse model of PD. In this article, we summarize recent progress in studies investigating the relationship between CART, dopamine, and the pathophysiology of PD, with a focus on mitochondria-related topics.
- Published
- 2013
43. Exercise intervention increases spontaneous locomotion but fails to attenuate dopaminergic system loss in a progressive MPTP model in aged mice
- Author
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Cynthia Moore, William A. Liguore, Charles K. Meshul, Lacey Pflibsen, and Rebecca L. Hood
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Aging ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Dopamine ,Striatum ,Neuroprotection ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Parkinsonian Disorders ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Exercise intervention ,General Neuroscience ,MPTP ,Dopaminergic Neurons ,Dopaminergic ,Motor Cortex ,Parkinson Disease ,medicine.disease ,Corpus Striatum ,Exercise Therapy ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,nervous system ,chemistry ,Neurology (clinical) ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Locomotion ,Developmental Biology ,medicine.drug ,Motor cortex - Abstract
While exercise is commonly recommended for PD patients to improve motor function, little is known about the disease-altering potential of exercise. Although others have demonstrated neuroprotective or neurorestorative effects of exercise in animal models of PD, the majority of these studies utilize young animals. In order to assess the effects of exercise intervention in a more clinically relevant model, we have subjected aged mice to progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioning and daily treadmill exercise, initiated early in the course of the disease. The MPTP model elicited a 55% reduction in striatal TH as measured by immunohistochemistry compared to sedentary controls, and exercise did not attenuate this loss in exercised MPTP animals. Furthermore, striatal TH and DAT loss, as assessed by western blotting, were not significantly impacted by treadmill exercise in MPTP-lesioned mice. We did find an increase in spontaneous locomotion in exercised mice that was not decreased by MPTP lesioning. This finding may be due, in part, to an increase in TH expression in the motor cortex in exercised MPTP mice.
- Published
- 2016
44. Social enrichment attenuates nigrostriatal lesioning and reverses motor impairment in a progressive 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease
- Author
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Michael F. Salvatore, Natalie R.S. Goldberg, Lacey Pflibsen, Charles K. Meshul, and Victoria Fields
- Subjects
medicine.medical_specialty ,Parkinson's disease ,Tyrosine 3-Monooxygenase ,Dopamine ,Cell Count ,Substantia nigra ,Striatum ,Environment ,Motor Activity ,lcsh:RC321-571 ,Levodopa ,Mice ,chemistry.chemical_compound ,Internal medicine ,Animals ,Medicine ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,MPTP ,Social enrichment ,Dopamine transporter ,Analysis of Variance ,Dose-Response Relationship, Drug ,biology ,Tyrosine hydroxylase ,business.industry ,Pars compacta ,Parkinson Disease ,medicine.disease ,Corpus Striatum ,Mice, Inbred C57BL ,Substantia Nigra ,Disease Models, Animal ,Endocrinology ,Gene Expression Regulation ,nervous system ,Neurology ,chemistry ,1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ,Anesthesia ,biology.protein ,business ,Psychomotor Performance ,medicine.drug - Abstract
Environmental enrichment has been shown to be both neuroprotective and neurorestorative in 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of Parkinson's disease (PD). However, whether social interaction or novel physical stimulation is responsible for this recovery is controversial. In the current study, we have investigated the effects of only social enrichment (SocE) in progressively MPTP-lesioned mice. After mice were lesioned using a progressively increased dose (4 mg/kg, 8 mg/kg, 16 mg/kg and 32 mg/kg; each dose daily for 5 days), the MPTP-induced behavioral deficits, after the 32 mg/kg dose, were reversed with acute l -DOPA. This acute behavioral recovery suggests that this progressive MPTP-induced neurodegeneration is an appropriate murine model of PD. Mice were housed four per cage for the first 2 weeks of progressive lesioning or vehicle treatment. After the 8 mg/kg MPTP dose (prior to SocE intervention) mice showed a significant decrease in rearing and foot fault behaviors (FF/BB) compared to the vehicle group. Additionally, there was a 38% decrease in mean number of tyrosine hydroxylase immunoreactive (TH-ir) substantia nigra pars compacta (SNpc) neurons/section, and a 50% decrease in the optical density of TH-ir dorsolateral caudate putamen (CPu) terminals compared to the vehicle group. Mice were then housed either two (socially limited environment; SLE) or twelve (SocE) mice per cage during continued MPTP lesioning for the next 2 weeks at 16 mg/kg and 32 mg/kg MPTP. MPTP treatment was then discontinued, while mice remained in the SLE or SocE cages for an additional week. Rearing behavior was further impaired in SLE-MPTP mice following progressive MPTP, accompanied by additional decreases in the mean number of TH-ir SNpc neurons/section and CPu TH-ir terminals. CPu TH and dopamine transporter (DAT) protein expression, as well as dopamine tissue and TH protein levels was significantly decreased compared to either vehicle group. However, the deficit in rearing behavior in SLE-MPTP mice was reversed with acute l -DOPA following the intervention period. SocE-MPTP mice showed rearing and FF/BB behaviors similar to vehicle levels, although FF/BB was not significantly different from pre-intervention levels. The reversal from pre-intervention rearing deficits was correlated with an attenuated decrease in the mean number of SNpc TH-ir neurons/section and CPu TH and DAT protein, and with a blocked decrease in CPu TH-ir terminals compared to pre-intervention levels. Our findings show that SocE mice not only resist further nigrostriatal lesioning and FF/BB deficit, but rearing behavior is recovered to the level of the vehicle group despite continued MPTP treatment. In contrast, SLE mice showed continued loss of nigrostriatal TH-ir and decline of motor behaviors with progressive MPTP. The data suggest that non-pharmacological intervention that started at an early stage of dopamine loss is effective at slowing or blocking further nigrostriatal degeneration.
- Published
- 2012
45. Effects of treadmill exercise on behavioral recovery and neural changes in the substantia nigra and striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse
- Author
-
Charles K. Meshul, Beth A. Smith, and Natalie R.S. Goldberg
- Subjects
Male ,medicine.medical_specialty ,Blotting, Western ,Presynaptic Terminals ,Substantia nigra ,Striatum ,Article ,Mice ,chemistry.chemical_compound ,Dopamine ,Physical Conditioning, Animal ,Internal medicine ,Neural Pathways ,medicine ,Animals ,Treadmill ,Molecular Biology ,Dopamine transporter ,biology ,Tyrosine hydroxylase ,Pars compacta ,business.industry ,General Neuroscience ,MPTP ,MPTP Poisoning ,Recovery of Function ,Corpus Striatum ,Exercise Therapy ,Mice, Inbred C57BL ,Substantia Nigra ,Endocrinology ,nervous system ,chemistry ,Exercise Test ,biology.protein ,Neurology (clinical) ,business ,Neuroscience ,Developmental Biology ,medicine.drug - Abstract
Our goal was to extend our understanding of the neural changes behind motor recovery with treadmill exercise in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse. We determined the extent of dopamine (DA) terminal changes using western immunoblotting [striatal dopamine transporter (DAT) and tyrosine hydroxylase (TH)] and alterations in the mean number of DA cells/section by immunohistochemistry and Nissl staining [TH-labeled cells and thionin-stained cells in the substantia nigra pars compacta (SN-PC)]. We measured recovery of gait performance and amount of spontaneous physical activity using the parallel rod activity chamber (PRAC). We hypothesized that the decrease in TH-labeled neurons in the SN-PC due to MPTP will be partially reversed by treadmill exercise, leading to recovery of motor behavior as measured by the PRAC. Following MPTP or vehicle administration, mice ran on the treadmill for 1 hour per day at 18 cm/s, 5 days per week. Results showed that treadmill exercise improves gait performance and increases physical activity while promoting increased protein expression of striatal DAT and TH. Exercise was effective for all mice, however effects of early treadmill-based intervention appear to have an additional and unique benefit in mice who received MPTP. We are the first to show that, even following a nearly 50% decrease in the mean number of TH-labeled neurons/section in the SN-PC following MPTP, treadmill exercise leads to an increase of neurons in the SN-PC and improved motor behavior.
- Published
- 2011
46. The role of exercise in facilitating basal ganglia function in Parkinson’s disease
- Author
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Giselle M. Petzinger, Ruth I. Wood, Daniel P. Holschneider, Beth E. Fisher, Brett T. Lund, Marta G. Vučković, Michael W. Jakowec, Charles K. Meshul, Garnik Akopian, and John P. Walsh
- Subjects
Parkinson's disease ,business.industry ,Bioinformatics ,medicine.disease ,Neuroprotection ,Article ,Neurotrophic factors ,Dopamine ,Basal ganglia ,Neuroplasticity ,Medicine ,Neurology (clinical) ,Animal studies ,business ,Motor learning ,Neuroscience ,medicine.drug - Abstract
SUMMARY Epidemiological and clinical studies have suggested that exercise is beneficial for patients with Parkinson’s disease (PD). Through research in normal (noninjured) animals, neuroscientists have begun to understand the mechanisms in the brain by which behavioral training and exercise facilitates improvement in motor behavior through modulation of neuronal function and structure, called experience-dependent neuroplasticity. Recent studies are beginning to reveal molecules and downstream signaling pathways that are regulated during exercise and motor learning in animal models of PD and that are important in driving protective and/or adaptive changes in neuronal connections of the basal ganglia and related circuitry. These molecules include the neurotransmitters dopamine and glutamate (and their respective receptors) as well as neurotrophic factors (brain-derived neurotrophic factor). In parallel, human exercise studies have been important in revealing ‘proof of concept’ including examining the types and parameters of exercise that are important for behavioral/functional improvements and brain changes; the feasibility of incorporating and maintaining an exercise program in individuals with motor disability; and, importantly, the translation and investigation of exercise effects observed in animal studies to exercise effects on brain and behavior in individuals with PD. In this article we highlight findings from both animal and human exercise studies that provide insight into brain changes of the basal ganglia and its related circuitry and that support potentially key parameters of exercise that may lead to long-term benefit and disease modification in PD. In addition, we discuss the current and future impact on patient care and point out gaps in our knowledge where continuing research is needed. Elucidation of exercise parameters important in driving neuroplasticity, as well as the accompanying mechanisms that underlie experience-dependent neuroplasticity may also provide insights towards new therapeutic targets, including neurorestorative and/or neuroprotective agents, for individuals with PD and related neurodegenerative disorders.
- Published
- 2011
47. Time-dependent changes in GLT-1 functioning in striatum of hemi-Parkinson rats
- Author
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Anneleen Schallier, Stéphanie Goursaud, Katia Vermoesen, Emmanuel Hermans, Charles K. Meshul, Ann Massie, and Yvette Michotte
- Subjects
medicine.medical_specialty ,Time Factors ,Parkinson's disease ,Dopamine ,Blotting, Western ,Striatum ,Biology ,Piperazines ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Glutamatergic ,Internal medicine ,Basal ganglia ,medicine ,Animals ,Parkinson Disease, Secondary ,Oxidopamine ,Medial forebrain bundle ,Neurotransmitter ,Chromatography, High Pressure Liquid ,Aspartic Acid ,Medial Forebrain Bundle ,Glutamate receptor ,Cell Biology ,medicine.disease ,Immunohistochemistry ,Corpus Striatum ,Rats ,Excitatory Amino Acid Transporter 1 ,Endocrinology ,Excitatory Amino Acid Transporter 2 ,chemistry ,Synaptosomes - Abstract
Striatal dopamine loss in Parkinson's disease is accompanied by a dysregulation of corticostriatal glutamatergic neurotransmission. Within this study, we investigated striatal expression and activity of the glial high-affinity Na+/K+-dependent glutamate transporters, GLT-1 and GLAST, in the 6-hydroxydopamine hemi-Parkinson rat model at different time points after unilateral 6-hydroxydopamine injection into the medial forebrain bundle. Using semi-quantitative Western blotting and an ex vivo D-[H-3]-aspartate uptake assay, we showed a time-dependent bilateral effect of unilateral 6-hydroxydopamine lesioning on the expression as well as activity of GLT-1. At 3 and 12 weeks post-lesion, striatal GLT-1 function was bilaterally upregulated whereas at 5 weeks there was no change. Even though our data do not allow a straightforward conclusion as for the role of glutamate transporters in the pathogenesis of the disease, they do clearly demonstrate a link between disturbed glutamatergic neurotransmission and glutamate transporter functioning in the striatum of a rat model for Parkinson's disease. (C) 2010 Elsevier Ltd. All rights reserved.
- Published
- 2010
48. MK-801 inhibits l-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism
- Author
-
Charles K. Meshul, S. Paul Berger, Jason R. Lewis, Akari M. Anderson, Steven W. Johnson, and Melanie A. Paquette
- Subjects
Male ,Dyskinesia, Drug-Induced ,Levodopa ,Time Factors ,Parkinson's disease ,Rotation ,Motor Activity ,Pharmacology ,Article ,Antiparkinson Agents ,Rats, Sprague-Dawley ,Cellular and Molecular Neuroscience ,Parkinsonian Disorders ,medicine ,Animals ,Oxidopamine ,Parkinsonism ,Antagonist ,Dextromethorphan ,medicine.disease ,Abnormal involuntary movement ,Rats ,Disease Models, Animal ,Dyskinesia ,NMDA receptor ,Dizocilpine Maleate ,medicine.symptom ,Psychology ,Excitatory Amino Acid Antagonists ,medicine.drug - Abstract
Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in L-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.
- Published
- 2010
49. 12.3 SYSTEM XC- AS A NOVEL MODULATOR OF CORTICOSTRIATAL NEUROTRANSMISSION
- Author
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Hideyo Sato, Laurence Ris, Cynthia Moore, Eduard Bentea, Rebecca L. Hood, Agnès Villers, Giulia Albertini, Charles K. Meshul, Lauren Deneyer, Ann Massie, Lise Verbruggen, and Madeline J Churchill
- Subjects
Concurrent Symposia ,Psychiatry and Mental health ,Electrophysiology ,Abstracts ,Dendritic spine ,Synaptic cleft ,Chemistry ,Excitatory postsynaptic potential ,Glutamate receptor ,Biophysics ,Hippocampus ,Neurotransmission ,Postsynaptic density - Abstract
Background System xc- is a plasma membrane amino acid antiporter, of mainly glial origin, that couples the import of cystine with the export of glutamate. System xc- (specific subunit xCT) contributes substantially to ambient extracellular glutamate levels in various regions of the brain, including the striatum and hippocampus. Despite the fact that system xc- is highly expressed in the brain and is a proposed therapeutic target for various neurological disorders, its function under physiological conditions in the central nervous system remains poorly understood. By acting as a source of glial extrasynaptic glutamate, system xc- might modulate synaptic transmission as a mechanism of neuro-glial communication. Previous electrophysiological findings indicate that system xc- delivered glutamate can inhibit excitatory synaptic neurotransmission in the corticoaccumbens pathway and at hippocampal CA3-CA1 synapses. To gain further insight into the proposed function of system xc- as modulator of synaptic transmission, we here focus on corticostriatal synapses. Methods Single section electron microscopy was carried out on VGLUT1-pre-embed and glutamate immunogold post-embed labeled slices of the dorsolateral striatum of xCT+/+ and xCT-/- mice. Various parameters related to the pre- and post-synaptic compartments were integrated on the obtained electron micrographs, including glutamate immunogold density in the presynaptic terminal and spine, area of the terminal and spine, measures of the postsynaptic density (PSD) (length, area, thickness, and maximum thickness), percentage of PSDs showing perforations, and width of the synaptic cleft. Electrophysiological measures of corticostriatal transmission were obtained by recording the amplitude of field excitatory postsynaptic potentials (fEPSPs) after stimulation of corticostriatal fibers. Finally, grooming behavior was compared between xCT-/- and xCT+/+ littermates. Results Genetic deletion of xCT led to depletion of glutamate immunogold labeling from corticostriatal terminals and their corresponding dendritic spines. Absence of xCT did not, however, affect the morphology of corticostriatal synapses, as evaluated by the area of the terminals and spines, size of the PSD, and width of the synaptic cleft. Similarly, no changes could be observed in the density of VGLUT1-positive synapses, indicating normal cortical innervation and spine density. Electrophysiological recordings revealed decreased amplitude of fEPSPs in xCT-/- mice after stimulation of corticostriatal fibers. Preliminary investigations revealed that this reduced response can be rescued by restoring physiological levels of glutamate to xCT-/- slices. Changes in corticostriatal transmission were not reflected in aberrant grooming behavior in xCT-/- mice; we could not observe any difference in the total grooming duration, the number of grooming bouts, the average bout duration or the latency to onset to grooming between xCT-/- and xCT+/+ mice. Discussion Contrary to available evidence at hippocampal and corticoaccumbens pathways, our findings indicate a positive effect of system xc- on basal synaptic transmission at corticostriatal synapses. The decreased response we observed after stimulation of corticostriatal fibers in xCT-/- mice was accompanied by depletion of glutamate immunogold labeling from corticostriatal terminals, suggesting a possible defect in presynaptic glutamate handling. Given the strong decrease (70%) in extracellular glutamate levels previously reported in this strain of mice, we hypothesize that the decreased presynaptic glutamate labeling in xCT-/- mice is related to a loss of extracellular glutamate needed to supply terminals for proper excitatory transmission. This hypothesis is supported by our preliminary results showing increased responses in xCT-/- slices after restoring physiological levels of glutamate. Together, our findings shed new light on the role of system xc- in controlling synaptic transmission, and suggest that it may play an important role in supplying presynaptic terminals with glutamate as an alternative mechanism to the glutamate-glutamine cycle. As a novel modulator of corticostriatal transmission, system xc- may be of interest as a possible therapeutic target for disorders with a corticostriatal component, such as schizophrenia or obsessive-compulsive disorder.
- Published
- 2018
50. Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinson's disease
- Author
-
Charles K. Meshul, S. Totterdell, Gloria E. Meredith, and Mitchell Beales
- Subjects
Male ,medicine.medical_specialty ,Programmed cell death ,Parkinson's disease ,Dopamine ,Excitotoxicity ,Biological Transport, Active ,Glutamic Acid ,Apoptosis ,Substantia nigra ,Biology ,medicine.disease_cause ,Article ,Mice ,chemistry.chemical_compound ,Parkinsonian Disorders ,Developmental Neuroscience ,Glutamate homeostasis ,Internal medicine ,Vesicular Glutamate Transport Proteins ,Autophagy ,medicine ,Animals ,Homeostasis ,Adjuvants, Pharmaceutic ,Neurons ,Probenecid ,MPTP ,Glutamate receptor ,Extracellular Fluid ,medicine.disease ,Up-Regulation ,Mice, Inbred C57BL ,Substantia Nigra ,Disease Models, Animal ,Endocrinology ,nervous system ,Neurology ,chemistry ,Signal Transduction ,medicine.drug - Abstract
The pathogenesis of Parkinson's disease is not fully understood, but there is evidence that excitotoxic mechanisms contribute to the pathology. However, data supporting a role for excitotoxicity in the pathophysiology of the disease are controversial and sparse. The goal of this study was to determine whether changes in glutamate signaling and uptake contribute to the demise of dopaminergic neurons in the substantia nigra. Mice were treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid or vehicle (probenecid or saline alone). Extracellular levels of glutamate in the substantia nigra were substantially increased, and there was an increase in the affinity, but no change in the velocity, of glutamate transport after MPTP/probenecid treatment compared to vehicle controls. In addition, the substantia nigra showed two types of programmed death, apoptosis (type I) and autophagic (type II) cell death. These data suggest that increased glutamate signaling could be an important mechanism for the death of dopaminergic neurons and trigger the induction of programmed cell death in the chronic MPTP/probenecid model.
- Published
- 2009
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