170 results on '"Lisa M. Monteggia"'
Search Results
2. Spatially non-overlapping Ca2+ signals drive distinct forms of neurotransmission
- Author
-
Camille S. Wang, Lisa M. Monteggia, and Ege T. Kavalali
- Subjects
CP: Neuroscience ,CP: Cell biology ,Biology (General) ,QH301-705.5 - Abstract
Summary: Calcium (Ca2+) signaling is tightly regulated within a presynaptic bouton. Here, we visualize Ca2+ signals within hippocampal presynaptic boutons using GCaMP8s tagged to synaptobrevin, a synaptic vesicle protein. We identify evoked presynaptic Ca2+ transients (ePreCTs) that derive from synchronized voltage-gated Ca2+ channel openings, spontaneous presynaptic Ca2+ transients (sPreCTs) that originate from ryanodine sensitive Ca2+ stores, and a baseline Ca2+ signal that arises from stochastic voltage-gated Ca2+ channel openings. We find that baseline Ca2+, but not sPreCTs, contributes to spontaneous glutamate release. We employ photobleaching as a use-dependent tool to probe nano-organization of Ca2+ signals and observe that all three occur in non-overlapping domains within the synapse at near-resting conditions. However, increased depolarization induces intermixing of these Ca2+ domains via both local and non-local synaptic vesicle turnover. Our findings reveal nanosegregation of Ca2+ signals within a presynaptic terminal that derive from multiple sources and in turn drive specific modes of neurotransmission.
- Published
- 2023
- Full Text
- View/download PDF
3. Neurotransmitter release progressively desynchronizes in induced human neurons during synapse maturation and aging
- Author
-
Burak Uzay, Aiden Houcek, Z. Zack Ma, Christine Konradi, Lisa M. Monteggia, and Ege T. Kavalali
- Subjects
CP: Neuroscience ,Biology (General) ,QH301-705.5 - Abstract
Summary: Rapid release of neurotransmitters in synchrony with action potentials is considered a key hardwired property of synapses. Here, in glutamatergic synapses formed between induced human neurons, we show that action potential-dependent neurotransmitter release becomes progressively desynchronized as synapses mature and age. In this solely excitatory network, the emergence of NMDAR-mediated transmission elicits endoplasmic reticulum (ER) stress leading to downregulation of key presynaptic molecules, synaptotagmin-1 and cysteine string protein α, that synchronize neurotransmitter release. The emergence of asynchronous release with neuronal maturity and subsequent aging is maintained by the high-affinity Ca2+ sensor synaptotagmin-7 and suppressed by the introduction of GABAergic transmission into the network, inhibition of NMDARs, and ER stress. These results suggest that long-term disruption of excitation-inhibition balance affects the synchrony of excitatory neurotransmission in human synapses.
- Published
- 2023
- Full Text
- View/download PDF
4. Optical analysis of AMPAR-mediated synaptic scaling in mouse hippocampus
- Author
-
Kanzo Suzuki, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
Cell Biology ,Microscopy ,Neuroscience ,Science (General) ,Q1-390 - Abstract
Summary: Immunolabeling of surface AMPA receptors (AMPARs) can be used for in vivo or ex vivo examination of synaptic scaling, a type of homeostatic plasticity. Here, we present a protocol to analyze changes in synaptic weights using immunohistochemistry for surface AMPARs coupled with optical imaging analysis. We detail immunostaining of AMPARs in mouse brain sections, followed by confocal imaging of surface AMPARs in dendritic region of hippocampal CA1. We then describe using Fiji/ImageJ and rank order plots for analyzing synaptic weight.For complete details on the use and execution of this protocol, please refer to Suzuki et al. (2021). : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
- Published
- 2022
- Full Text
- View/download PDF
5. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action
- Author
-
Kanzo Suzuki, Ji-Woon Kim, Elena Nosyreva, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
eEF2K ,RARα ,synaptic scaling ,rapid antidepressant action ,Biology (General) ,QH301-705.5 - Abstract
Summary: Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.
- Published
- 2021
- Full Text
- View/download PDF
6. Genetic Dissection of Presynaptic and Postsynaptic BDNF-TrkB Signaling in Synaptic Efficacy of CA3-CA1 Synapses
- Author
-
Pei-Yi Lin, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Summary: Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), regulate long-term potentiation (LTP) in the hippocampus, although the sites of BDNF-TrkB receptors in this process are controversial. We used a viral-mediated approach to delete BDNF or TrkB specifically in CA1 and CA3 regions of the Schaffer collateral pathway. Deletion of BDNF in CA3 or CA1 revealed that presynaptic BDNF is involved in LTP induction, while postsynaptic BDNF contributes to LTP maintenance. Similarly, loss of presynaptic or postsynaptic TrkB receptors leads to distinct LTP deficits, with presynaptic TrkB required to maintain LTP, while postsynaptic TrkB is essential for LTP formation. In addition, loss of TrkB in CA3 significantly diminishes release probability, uncovering a role for presynaptic TrkB receptors in basal neurotransmission. Taken together, this direct comparison of presynaptic and postsynaptic BDNF-TrkB reveals insight into BDNF release and TrkB activation sites in hippocampal LTP. : Lin et al. directly compare a role for presynaptic and postsynaptic BDNF and TrkB receptors in hippocampal LTP. They find that LTP induction is mediated by anterograde BDNF-TrkB signaling, while both anterograde and retrograde BDNF-TrkB signaling persists presynaptically and postsynaptically for LTP maintenance. Keywords: BDNF, TrkB, hippocampus, synaptic plasticity, LTP, presynaptic, postsynaptic
- Published
- 2018
- Full Text
- View/download PDF
7. Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy
- Author
-
Devon C. Crawford, Denise M. O. Ramirez, Brent Trauterman, Lisa M. Monteggia, and Ege T. Kavalali
- Subjects
Science - Abstract
Emerging evidence suggests that spontaneous neurotransmitter release contributes to the maintenance of synaptic efficacy. Here the authors selectively reduce spontaneous glutamatergic transmission while leaving the stimulus-evoked responses intact and show that this leads to homeostatic scaling at the postsynaptic side in cultured neurons and alters synaptic plasticity in acute brain slices.
- Published
- 2017
- Full Text
- View/download PDF
8. Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor
- Author
-
Camille S Wang, Natali L Chanaday, Lisa M Monteggia, and Ege T Kavalali
- Subjects
synaptic transmission ,glutamate release ,spontaneous release ,evoked release ,fluorescence photobleaching ,iGluSnFR ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Synapses maintain both action potential-evoked and spontaneous neurotransmitter release; however, organization of these two forms of release within an individual synapse remains unclear. Here, we used photobleaching properties of iGluSnFR, a fluorescent probe that detects glutamate, to investigate the subsynaptic organization of evoked and spontaneous release in primary hippocampal cultures. In nonneuronal cells and neuronal dendrites, iGluSnFR fluorescence is intensely photobleached and recovers via diffusion of nonphotobleached probes with a time constant of ~10 s. After photobleaching, while evoked iGluSnFR events could be rapidly suppressed, their recovery required several hours. In contrast, iGluSnFR responses to spontaneous release were comparatively resilient to photobleaching, unless the complete pool of iGluSnFR was activated by glutamate perfusion. This differential effect of photobleaching on different modes of neurotransmission is consistent with a subsynaptic organization where sites of evoked glutamate release are clustered and corresponding iGluSnFR probes are diffusion restricted, while spontaneous release sites are broadly spread across a synapse with readily diffusible iGluSnFR probes.
- Published
- 2022
- Full Text
- View/download PDF
9. Bridging rapid and sustained antidepressant effects of ketamine
- Author
-
Ji-Woon Kim, Kanzo Suzuki, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
Molecular Medicine ,Molecular Biology - Published
- 2023
10. Spontaneous and evoked neurotransmission are partially segregated at inhibitory synapses
- Author
-
Patricia M Horvath, Michelle K Piazza, Lisa M Monteggia, and Ege T Kavalali
- Subjects
spontaneous release ,GABAergic neurotransmission ,picrotoxin ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Synaptic transmission is initiated via spontaneous or action-potential evoked fusion of synaptic vesicles. At excitatory synapses, glutamatergic receptors activated by spontaneous and evoked neurotransmission are segregated. Although inhibitory synapses also transmit signals spontaneously or in response to action potentials, they differ from excitatory synapses in both structure and function. Therefore, we hypothesized that inhibitory synapses may have different organizing principles. We report picrotoxin, a GABAAR antagonist, blocks neurotransmission in a use-dependent manner at rat hippocampal synapses and therefore can be used to interrogate synaptic properties. Using this tool, we uncovered partial segregation of inhibitory spontaneous and evoked neurotransmission. We found up to 40% of the evoked response is mediated through GABAARs which are only activated by evoked neurotransmission. These data indicate GABAergic spontaneous and evoked neurotransmission processes are partially non-overlapping, suggesting they may serve divergent roles in neuronal signaling.
- Published
- 2020
- Full Text
- View/download PDF
11. <scp>MeCP2</scp> loss‐of‐function dysregulates <scp>microRNAs</scp> regionally and disrupts excitatory/inhibitory synaptic transmission balance
- Author
-
Patricia M. Horvath, Michelle K. Piazza, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
Mice, Knockout ,Mice ,MicroRNAs ,Methyl-CpG-Binding Protein 2 ,Cognitive Neuroscience ,Synapses ,Rett Syndrome ,Animals ,Female ,Synaptic Transmission - Abstract
Rett syndrome is a leading cause of intellectual disability in females primarily caused by loss of function mutations in the transcriptional regulator MeCP2. Loss of MeCP2 leads to a host of synaptic phenotypes that are believed to underlie Rett syndrome pathophysiology. Synaptic deficits vary by brain region upon MeCP2 loss, suggesting distinct molecular alterations leading to disparate synaptic outcomes. In this study, we examined the contribution of MeCP2's newly described role in miRNA regulation to regional molecular and synaptic impairments. Two miRNAs, miR-101a and miR-203, were identified and confirmed as upregulated in MeCP2 KO mice in the hippocampus and cortex, respectively. miR-101a overexpression in hippocampal cultures led to opposing effects at excitatory and inhibitory synapses and in spontaneous and evoked neurotransmission, revealing the potential for a single miRNA to broadly regulate synapse function in the hippocampus. These results highlight the importance of regional alterations in miRNA expression and the specific impact on synaptic function with potential implications for Rett syndrome.
- Published
- 2022
12. NPP’s approach toward improving rigor and transparency in clinical trials research
- Author
-
Sofiya Hupalo, Chloe J. Jordan, Terri Bowen, Jennifer Mahar, Elizabeth Yepez, Lori Kunath, Sarah Timm, Keri Martinowich, William A. Carlezon, Lisa M. Monteggia, and Tony P. George
- Subjects
Pharmacology ,Psychiatry and Mental health - Published
- 2022
13. Correction: D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome.
- Author
-
Elisa S Na, Héctor De Jesús-Cortés, Arlene Martinez-Rivera, Zeeba D Kabir, Jieqi Wang, Vijayashree Ramesh, Yasemin Onder, Anjali M Rajadhyaksha, Lisa M Monteggia, and Andrew A Pieper
- Subjects
Medicine ,Science - Abstract
[This corrects the article DOI: 10.1371/journal.pone.0183026.].
- Published
- 2018
- Full Text
- View/download PDF
14. The times they are a-changin': new co-principal editors at NPP
- Author
-
Tony P. George and Lisa M. Monteggia
- Subjects
Pharmacology ,Psychiatry and Mental health - Published
- 2022
15. Sustained effects of rapidly-acting antidepressants require BDNF-dependent MeCP2 phosphorylation
- Author
-
Megumi Adachi, Anita E. Autry, Ji Woon Kim, Elisa S. Na, Carl Björkholm, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
0301 basic medicine ,Methyl-CpG-Binding Protein 2 ,Scopolamine ,Article ,MECP2 ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Ketamine ,Phosphorylation ,Mice, Knockout ,Neuronal Plasticity ,business.industry ,Extramural ,Brain-Derived Neurotrophic Factor ,General Neuroscience ,Brain ,Antidepressive Agents ,Mice, Inbred C57BL ,030104 developmental biology ,Synaptic plasticity ,Antidepressant ,business ,Neuroscience ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The rapidly acting antidepressants ketamine and scopolamine exert behavioral effects that can last from several days to more than a week in some patients. The molecular mechanisms underlying the maintenance of these antidepressant effects are unknown. Here we show that methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) is essential for the sustained, but not the rapid, antidepressant effects of ketamine and scopolamine in mice. Our results reveal that pMeCP2 is downstream of BDNF, a critical factor in ketamine and scopolamine antidepressant action. In addition, we show that pMeCP2 is required for the long-term regulation of synaptic strength after ketamine or scopolamine administration. These results demonstrate that pMeCP2 and associated synaptic plasticity are essential determinants of sustained antidepressant effects.
- Published
- 2021
16. Chronic lithium treatment elicits its antimanic effects via BDNF-TrkB dependent synaptic downscaling
- Author
-
Erinn S Gideons, Pei-Yi Lin, Melissa Mahgoub, Ege T Kavalali, and Lisa M Monteggia
- Subjects
lithium ,bdnf ,dynamin ,endocytosis ,mania ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Lithium is widely used as a treatment for Bipolar Disorder although the molecular mechanisms that underlie its therapeutic effects are under debate. In this study, we show brain-derived neurotrophic factor (BDNF) is required for the antimanic-like effects of lithium but not the antidepressant-like effects in mice. We performed whole cell patch clamp recordings of hippocampal neurons to determine the impact of lithium on synaptic transmission that may underlie the behavioral effects. Lithium produced a significant decrease in α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated miniature excitatory postsynaptic current (mEPSC) amplitudes due to postsynaptic homeostatic plasticity that was dependent on BDNF and its receptor tropomyosin receptor kinase B (TrkB). The decrease in AMPAR function was due to reduced surface expression of GluA1 subunits through dynamin-dependent endocytosis. Collectively, these findings demonstrate a requirement for BDNF in the antimanic action of lithium and identify enhanced dynamin-dependent endocytosis of AMPARs as a potential mechanism underlying the therapeutic effects of lithium.
- Published
- 2017
- Full Text
- View/download PDF
17. Rapid homeostatic plasticity and neuropsychiatric therapeutics
- Author
-
Ege T. Kavalali and Lisa M. Monteggia
- Subjects
Pharmacology ,Neurons ,Psychiatry and Mental health ,Neuronal Plasticity ,Synapses ,Homeostasis ,Ketamine - Abstract
Neuronal and synaptic plasticity are widely used terms in the field of psychiatry. However, cellular neurophysiologists have identified two broad classes of plasticity. Hebbian forms of plasticity alter synaptic strength in a synapse specific manner in the same direction of the initial conditioning stimulation. In contrast, homeostatic plasticities act globally over longer time frames in a negative feedback manner to counter network level changes in activity or synaptic strength. Recent evidence suggests that homeostatic plasticity mechanisms can be rapidly engaged, particularly by fast-acting antidepressants such as ketamine to trigger behavioral effects. There is increasing evidence that several neuropsychoactive compounds either directly elicit changes in synaptic activity or indirectly tap into downstream signaling pathways to trigger homeostatic plasticity and subsequent behavioral effects. In this review, we discuss this recent work in the context of a wider paradigm where homeostatic synaptic plasticity mechanisms may provide novel targets for neuropsychiatric treatment advance.
- Published
- 2022
18. Author response: Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor
- Author
-
Camille S Wang, Natali L Chanaday, Lisa M Monteggia, and Ege T Kavalali
- Published
- 2022
19. Behavioral Analysis of SNAP-25 and Synaptobrevin-2 Haploinsufficiency in Mice
- Author
-
Megumi Adachi, Pei-Yi Lin, Lisa M. Monteggia, and Ege T. Kavalali
- Subjects
0301 basic medicine ,Nervous system ,Synaptosomal-Associated Protein 25 ,Vesicle-Associated Membrane Protein 2 ,Haploinsufficiency ,Neurotransmission ,Biology ,Synaptic vesicle ,Article ,Exocytosis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Prepulse inhibition ,Behavior, Animal ,General Neuroscience ,SNAP25 ,Mice, Mutant Strains ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Hypoactivity ,030217 neurology & neurosurgery - Abstract
In central synapses, synaptobrevin-2 (also called VAMP-2) is the predominant synaptic vesicle SNARE protein that interacts with the plasma membrane SNAREs, SNAP-25 and syntaxin-1 to execute exocytosis. Mice deficient in synaptobrevin-2 or SNAP-25 show embryonic lethality, which precludes investigation of the complete loss-of-function of these proteins in the adult nervous system. However, mice that carry heterozygous null mutations survive into adulthood and are fertile. In order to elucidate how loss-of-function mutations in these proteins may result in human disease phenotypes it is important to develop bona fide animal models. Therefore, given the importance of these two critical SNAREs in central synaptic transmission and their association with several neurological or neuropsychiatric disorders, we performed a comprehensive behavioral analysis of SNAP-25 heterozygous null (SNAP25(+/−)) mice as well as the synaptobrevin-2 heterozygous null (+/−) mice. This analysis revealed only mild phenotypes, SNAP-25 (+/−) mice exhibited marked hypoactivity, whereas synaptobrevin-2 (+/−) mice showed enhanced performance on the rotarod. The two mouse lines did not manifest significant deficits in anxiety-related behaviors, learning and memory measures, or prepulse inhibition. The rather mild behavioral deficits indicate that these key proteins, SNAP25 and synaptobrevin-2, are expressed in excess to circumvent the impact of potential fluctuations in expression levels on nervous system function.
- Published
- 2019
20. Probing the segregation of evoked and spontaneous neurotransmission via photobleaching and recovery of a fluorescent glutamate sensor
- Author
-
Camille S Wang, Natali L Chanaday, Lisa M Monteggia, and Ege T Kavalali
- Subjects
Photobleaching ,General Immunology and Microbiology ,General Neuroscience ,Synapses ,Glutamic Acid ,General Medicine ,Hippocampus ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology - Abstract
Synapses maintain both action potential-evoked and spontaneous neurotransmitter release; however, organization of these two forms of release within an individual synapse remains unclear. Here, we used photobleaching properties of iGluSnFR, a fluorescent probe that detects glutamate, to investigate the subsynaptic organization of evoked and spontaneous release in primary hippocampal cultures. In nonneuronal cells and neuronal dendrites, iGluSnFR fluorescence is intensely photobleached and recovers via diffusion of nonphotobleached probes with a time constant of ~10 s. After photobleaching, while evoked iGluSnFR events could be rapidly suppressed, their recovery required several hours. In contrast, iGluSnFR responses to spontaneous release were comparatively resilient to photobleaching, unless the complete pool of iGluSnFR was activated by glutamate perfusion. This differential effect of photobleaching on different modes of neurotransmission is consistent with a subsynaptic organization where sites of evoked glutamate release are clustered and corresponding iGluSnFR probes are diffusion restricted, while spontaneous release sites are broadly spread across a synapse with readily diffusible iGluSnFR probes.
- Published
- 2021
21. Editor's evaluation: A bidirectional switch in the Shank3 phosphorylation state biases synapses toward up- or downscaling
- Author
-
Lisa M Monteggia
- Published
- 2021
22. BDNF signaling in context: From synaptic regulation to psychiatric disorders
- Author
-
Camille S. Wang, Ege T. Kavalali, and Lisa M. Monteggia
- Subjects
Psychotropic Drugs ,Neuronal Plasticity ,Brain-Derived Neurotrophic Factor ,Mental Disorders ,Neurogenesis ,Neuropeptides ,Brain ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology ,Article ,Treatment Outcome ,Synapses ,Animals ,Homeostasis ,Humans - Abstract
Brain derived neurotrophic factor (BDNF) is a neuropeptide that plays numerous important roles in synaptic development and plasticity. While its importance in fundamental physiology is well-established, studies of BDNF often produce conflicting and unclear results, and the scope of existing research makes the prospect of setting future directions difficult. In this review, we examine the importance of spatial and temporal factors on BDNF activity, particularly in processes such as synaptogenesis, Hebbian plasticity, homeostatic plasticity, and the treatment of psychiatric disorders. Understanding the fundamental physiology of when, where, and how BDNF acts and new approaches to control BDNF signaling in time and space can contribute to improved therapeutics and patient outcomes.
- Published
- 2021
23. A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action
- Author
-
Ege T. Kavalali, Ji Woon Kim, Lisa M. Monteggia, and Joachim Herz
- Subjects
Male ,Low-density lipoprotein receptor-related protein 8 ,Neurotransmission ,Receptors, N-Methyl-D-Aspartate ,Mice ,Phosphatidylinositol 3-Kinases ,Postsynaptic potential ,Animals ,Reelin ,LDL-Receptor Related Proteins ,Multidisciplinary ,Neuronal Plasticity ,biology ,Behavior, Animal ,Biological Sciences ,DAB1 ,Antidepressive Agents ,Reelin Protein ,src-Family Kinases ,nervous system ,Synaptic plasticity ,biology.protein ,NMDA receptor ,Ketamine ,Synaptic signaling ,Neuroscience ,Signal Transduction - Abstract
Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant action in some patients with treatment-resistant depression. However, recent data suggest that ∼50% of patients with treatment-resistant depression do not respond to ketamine. The factors that contribute to the nonresponsiveness to ketamine's antidepressant action remain unclear. Recent studies have reported a role for secreted glycoprotein Reelin in regulating pre- and postsynaptic function, which suggests that Reelin may be involved in ketamine's antidepressant action, although the premise has not been tested. Here, we investigated whether the disruption of Reelin-mediated synaptic signaling alters ketamine-triggered synaptic plasticity and behavioral effects. To this end, we used mouse models with genetic deletion of Reelin or apolipoprotein E receptor 2 (Apoer2), as well as pharmacological inhibition of their downstream effectors, Src family kinases (SFKs) or phosphoinositide 3-kinase. We found that disruption of Reelin, Apoer2, or SFKs blocks ketamine-driven behavioral changes and synaptic plasticity in the hippocampal CA1 region. Although ketamine administration did not affect tyrosine phosphorylation of DAB1, an adaptor protein linked to downstream signaling of Reelin, disruption of Apoer2 or SFKs impaired baseline NMDA receptor-mediated neurotransmission. These results suggest that maintenance of baseline NMDA receptor function by Reelin signaling may be a key permissive factor required for ketamine's antidepressant effects. Taken together, our results suggest that impairments in Reelin-Apoer2-SFK pathway components may in part underlie nonresponsiveness to ketamine's antidepressant action.
- Published
- 2021
24. Brain-Derived Neurotrophic Factor Signaling in Depression and Antidepressant Action
- Author
-
Eero Castrén and Lisa M. Monteggia
- Subjects
0301 basic medicine ,Tropomyosin receptor kinase B ,Receptor tyrosine kinase ,03 medical and health sciences ,0302 clinical medicine ,Neurotrophic factors ,Neuroplasticity ,Medicine ,Humans ,Receptor, trkB ,Biological Psychiatry ,Brain-derived neurotrophic factor ,biology ,business.industry ,Depression ,Mood Disorders ,Brain-Derived Neurotrophic Factor ,medicine.disease ,Antidepressive Agents ,030104 developmental biology ,nervous system ,Mood disorders ,biology.protein ,Antidepressant ,business ,Neuroscience ,030217 neurology & neurosurgery ,Neurotrophin ,Signal Transduction - Abstract
Neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), have been associated with depression and antidepressant drug action. A variety of preclinical and clinical studies have implicated impaired BDNF signaling through its receptor TrkB (neurotrophic receptor tyrosine kinase 2) in the pathophysiology of mood disorders, but many of the initial findings have not been fully supported by more recent meta-analyses, and more both basic and clinical research is needed. In contrast, increased expression and signaling of BDNF has been repeatedly implicated in the mechanisms of both typical and rapid-acting antidepressant drugs, and recent findings have started to elucidate the mechanisms through which antidepressants regulate BDNF signaling. BDNF is a critical regulator of various types of neuronal plasticities in the brain, and plasticity has increasingly been connected with antidepressant action. Although some equivocal data exist, the hypothesis of a connection between neurotrophic factors and neuronal plasticity with mood disorders and antidepressant action has recently been further strengthened by converging evidence from a variety of more recent data reviewed here.
- Published
- 2021
25. The role of eEF2 kinase in the rapid antidepressant actions of ketamine
- Author
-
Kanzo, Suzuki and Lisa M, Monteggia
- Subjects
Elongation Factor 2 Kinase ,Neuronal Plasticity ,Depression ,Animals ,Humans ,Ketamine ,Receptors, N-Methyl-D-Aspartate ,Antidepressive Agents - Abstract
Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.
- Published
- 2020
26. Persistence of quantal synaptic vesicle recycling following dynamin depletion
- Author
-
Natali L. Chanaday, Lisa M. Monteggia, Ege T. Kavalali, O. Afuwape, and M. Kasap
- Subjects
Chemistry ,Vesicle ,Endocytic cycle ,Synaptic vesicle recycling ,GTPase ,Neurotransmission ,Endocytosis ,Synaptic vesicle ,Cell biology ,Dynamin - Abstract
Dynamins are GTPases required for pinching vesicles off the plasma membrane once a critical curvature is reached during endocytosis. Here, we probed dynamin function in central synapses by depleting all three dynamin isoforms in postnatal hippocampal neurons. We found a decrease in the propensity of evoked neurotransmission as well as a reduction in synaptic vesicle numbers. Using the fluorescent reporter vGluT1-pHluorin, we observed that compensatory endocytosis after 20 Hz stimulation was arrested in ~40% of presynaptic boutons, while remaining synapses showed only a modest effect suggesting the existence of a dynamin-independent endocytic pathway in central synapses. Surprisingly, we found that the retrieval of single synaptic vesicles, after either evoked or spontaneous fusion, was largely impervious to disruption of dynamins. Overall, our results suggest that classical dynamin-dependent endocytosis is not essential for retrieval of synaptic vesicle proteins after quantal single synaptic vesicle fusion.
- Published
- 2020
27. Role of Aberrant Spontaneous Neurotransmission in SNAP25-Associated Encephalopathies
- Author
-
Lisa M. Monteggia, Rong Sun, Ok-Ho Shin, Pei-Yi Lin, K Ian White, Baris Alten, Qiangjun Zhou, Axel T. Brunger, Ege T. Kavalali, Luis Esquivies, and Wendy K. Chung
- Subjects
0301 basic medicine ,Male ,Adolescent ,Synaptosomal-Associated Protein 25 ,Synaptobrevin ,Mice, Transgenic ,Haploinsufficiency ,Neurotransmission ,Biology ,Synaptic Transmission ,Synaptotagmin 1 ,Protein Structure, Secondary ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Syntaxin ,Animals ,Humans ,Amino Acid Sequence ,Neurotransmitter ,Receptor ,Child ,Cells, Cultured ,Mice, Knockout ,Brain Diseases ,General Neuroscience ,SNAP25 ,Phenotype ,Rats ,030104 developmental biology ,HEK293 Cells ,chemistry ,Child, Preschool ,Female ,Neuroscience ,030217 neurology & neurosurgery - Abstract
SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) complex, composed of synaptobrevin, syntaxin, and SNAP25, forms the essential fusion machinery for neurotransmitter release. Recent studies have reported several mutations in the gene encoding SNAP25 as a causative factor for developmental and epileptic encephalopathies of infancy and childhood with diverse clinical manifestations. However, it remains unclear how SNAP25 mutations give rise to these disorders. Here, we show that although structurally clustered mutations in SNAP25 give rise to related synaptic transmission phenotypes, specific alterations in spontaneous neurotransmitter release are a key factor to account for disease heterogeneity. Importantly, we identified a single mutation that augments spontaneous release without altering evoked release, suggesting that aberrant spontaneous release is sufficient to cause disease in humans.
- Published
- 2020
28. Targeting homeostatic synaptic plasticity for treatment of mood disorders
- Author
-
Lisa M. Monteggia and Ege T. Kavalali
- Subjects
0301 basic medicine ,Bipolar Disorder ,Lithium (medication) ,medicine.drug_class ,Biology ,Article ,03 medical and health sciences ,Depressive Disorder, Treatment-Resistant ,0302 clinical medicine ,Antimanic Agents ,Homeostatic plasticity ,medicine ,Animals ,Homeostasis ,Humans ,Depressive Disorder, Major ,Synaptic scaling ,Neuronal Plasticity ,Mood Disorders ,General Neuroscience ,Mood stabilizer ,Cognition ,medicine.disease ,030104 developmental biology ,Mood disorders ,Synaptic plasticity ,Synapses ,Lithium Compounds ,Antidepressant ,Ketamine ,Neuroscience ,Excitatory Amino Acid Antagonists ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.
- Published
- 2020
29. Author response: Spontaneous and evoked neurotransmission are partially segregated at inhibitory synapses
- Author
-
Patricia M. Horvath, Ege T. Kavalali, Michelle K Piazza, and Lisa M. Monteggia
- Subjects
Chemistry ,Inhibitory synapses ,Neurotransmission ,Neuroscience - Published
- 2020
30. Decision letter: A role for CIM6P/IGF2 receptor in memory consolidation and enhancement
- Author
-
Kobi Rosenblum and Lisa M. Monteggia
- Subjects
Computer science ,Memory consolidation ,Receptor ,Neuroscience - Published
- 2020
31. List of contributors
- Author
-
Nicholas Ah Mew, Wado Akamatsu, Hasan Orhan Akman, Afnan AlHakeem, Koji Aoyama, Rafael Artuch, Michael Beck, C. Frank Bennett, Gerard T. Berry, D. Montgomery Bissell, Brenda Canine, C. Thomas Caskey, Widler Casy, Patrick F. Chinnery, David T. Chuang, Emily K. Cook, Rody P. Cox, Philip L. De Jager, Didem Demirbas, Robert J. Desnick, Salvatore DiMauro, Florian S. Eichler, Bernice Elger, Valentina Emmanuele, Patricia Evans, Brent L. Fogel, Àngels García-Cazorla, Cinzia Gellera, Sailaja Golla, Kimberly Goodspeed, Sidney M. Gospe, Steven J. Gray, Andrea L. Gropman, Yian Gu, Renzo Guerrini, Teresa M. Gunn, Una Hadziahmetovic, Darrah Haffner, R.J. Hagerman, Tamar Harel, Elizabeth Head, Rita Horvath, Yasushi Hosoi, Ying-Chen Claire Hou, Jane Hsiao, Hiroyuki Ishiura, Clifford R. Jack, Vikram Jakkamsetti, William G. Johnson†, Fabrice Jotterand, John P. Kane, Olga Khorkova, Chisato Kinoshita, Sanne E. Klompe, Lisa M. Koehl, Michael C. Kruer, Walter A. Kukull, Roger M. Lane, Joseph H. Lee, M.J. Leigh, Qinglan Ling, James R. Lupski, Paola Luzi, Qian Ma, Gustavo H.B. Maegawa, Mary J. Malloy, Seth S. Margolis, Isaac Marin-Valencia, James A. Mastrianni, Dena Matalon, Reuben Matalon, Kimberlee Michals Matalon Rd, Jennifer M. Mathews, Richard Mayeux, Jennifer McCurdy, Meira R. Meltzer, John H. Menkes†, Justin Miron, Jun Mitsui, Hiroaki Miyajima, Lisa M. Monteggia, Mary Ann Morris, Hugo W. Moser†, Melissa E. Murray, Toshio Nakaki, Nathalie Nilsson, Ichizo Nishino, Sandra M.H. Nordlie, Robert L. Nussbaum, William L. Nyhan, Hideyuki Okano, Sergio Padilla-Lopez, Elena Parrini, Juan M. Pascual, Gregory M. Pastores, Shailendra B. Patel, Marc C. Patterson, Izabella A. Pena, Cynthia Picard, Judes Poirier, Jennifer E. Posey, Gerald V. Raymond, William Renthal, David S. Rosenblatt, Francis Rossignol, Gerald Salen, Konrad Sandhoff, Raphael Schiffmann, Detlev Schindler, Frederick A. Schmitt, Susanne A. Schneider, Eric A. Schon, Edward H. Schuchman, Margretta Reed Seashore, Frances C. Shaffo, Michael Shevell, Sarah E. Sinnett, Myriam Srour, Samuel H. Sternberg, Kazuma Sugie, Kristen L. Szabla, Franco Taroni, Marina Tedeschi Dauar, Shoji Tsuji, Wendy R. Uhlmann, Clara van Karnebeek, Kathryn L. Van Pelt, Prashanthi Vemuri, Charles P. Venditti, Claes Wahlestedt, Bruce Wang, David Watkins, David A. Wenger, Charles A. Williams, Golder N. Wilson, Barry Wolf, R. Max Wynn, and Hung-Chun Yu
- Published
- 2020
32. The role of eEF2 kinase in the rapid antidepressant actions of ketamine
- Author
-
Kanzo Suzuki and Lisa M. Monteggia
- Subjects
business.industry ,Neurotrophic factors ,Spontaneous synaptic transmission ,Synaptic plasticity ,Medicine ,NMDA receptor ,Major depressive disorder ,Antidepressant ,Long-term potentiation ,AMPA receptor ,business ,medicine.disease ,Neuroscience - Abstract
Major depressive disorder is a prevalent and serious form of mental illness. While traditional antidepressants ameliorate some of the symptoms associated with depression, the onset of action typically takes several weeks leaving severely depressed individuals vulnerable to self-injurious behavior and possibly suicide. There has been a major unmet need for the development of pharmacological therapies that can quickly alleviate symptoms associated with depression. Clinical data shows that a single sub-psychomimetic dose of ketamine, a noncompetitive glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid antidepressant responses in patients with treatment-resistant major depressive disorder. We have studied key signaling pathways and synaptic mechanisms underlying the rapid antidepressant action of ketamine. Our studies show ketamine blocks synaptic NMDA receptors involved in spontaneous synaptic transmission, which deactivates calcium/calmodulin-dependent kinase eukaryotic elongation factor 2 kinase (eEF2K), resulting in dephosphorylation of eukaryotic elongation factor 2 (eEF2), and the subsequent desuppression of brain-derived neurotrophic factor (BDNF) protein synthesis in the hippocampus. This signaling pathway then potentiates synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor responses that results in a novel form of synaptic potentiation which corresponds with antidepressant efficacy. In this chapter, we focus on our studies examining ketamine's action and the instructive role of eEF2K in rapid antidepressant action. Our recent studies highlight eEF2K as a major molecular substrate mediating synaptic plasticity and the rapid antidepressant effects of ketamine.
- Published
- 2020
33. An overview of Rett syndrome
- Author
-
William Renthal, Kristen L. Szabla, and Lisa M. Monteggia
- Published
- 2020
34. Genetic Dissection of Presynaptic and Postsynaptic BDNF-TrkB Signaling in Synaptic Efficacy of CA3-CA1 Synapses
- Author
-
Lisa M. Monteggia, Ege T. Kavalali, and Pei-Yi Lin
- Subjects
0301 basic medicine ,Tropomyosin receptor kinase B ,Neurotransmission ,Receptors, Presynaptic ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Postsynaptic potential ,Neurotrophic factors ,LTP induction ,medicine ,Animals ,Humans ,Receptor, trkB ,lcsh:QH301-705.5 ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Synaptic Potentials ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,nervous system ,Schaffer collateral ,Synapses ,embryonic structures ,Synaptic plasticity ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
SUMMARY Brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, tropomyosin receptor kinase B (TrkB), regulate long-term potentiation (LTP) in the hippocampus, although the sites of BDNF-TrkB receptors in this process are controversial. We used a viral-mediated approach to delete BDNF or TrkB specifically in CA1 and CA3 regions of the Schaffer collateral pathway. Deletion of BDNF in CA3 or CA1 revealed that presynaptic BDNF is involved in LTP induction, while postsynaptic BDNF contributes to LTP maintenance. Similarly, loss of presynaptic or postsynaptic TrkB receptors leads to distinct LTP deficits, with presynaptic TrkB required to maintain LTP, while postsynaptic TrkB is essential for LTP formation. In addition, loss of TrkB in CA3 significantly diminishes release probability, uncovering a role for presynaptic TrkB receptors in basal neurotransmission. Taken together, this direct comparison of presynaptic and postsynaptic BDNF-TrkB reveals insight into BDNF release and TrkB activation sites in hippocampal LTP., In Brief Lin et al. directly compare a role for presynaptic and postsynaptic BDNF and TrkB receptors in hippocampal LTP. They find that LTP induction is mediated by anterograde BDNF-TrkB signaling, while both anterograde and retrograde BDNFTrkB signaling persists presynaptically and postsynaptically for LTP maintenance., Graphical Abstract
- Published
- 2018
35. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action
- Author
-
Ji-Woon Kim, Kanzo Suzuki, Ege T. Kavalali, Elena Nosyreva, and Lisa M. Monteggia
- Subjects
Elongation Factor 2 Kinase ,Male ,Time Factors ,QH301-705.5 ,Retinoic acid ,Hippocampus ,Tretinoin ,Synaptic Transmission ,Article ,General Biochemistry, Genetics and Molecular Biology ,Glutamatergic ,chemistry.chemical_compound ,rapid antidepressant action ,synaptic scaling ,Animals ,Humans ,Biology (General) ,CA1 Region, Hippocampal ,Mice, Knockout ,Neurons ,Neuronal Plasticity ,Synaptic scaling ,Chemistry ,Retinoic Acid Receptor alpha ,eEF2K ,Antidepressive Agents ,RARα ,Mice, Inbred C57BL ,Retinoic acid receptor ,HEK293 Cells ,Synapses ,Antidepressant ,NMDA receptor ,Ketamine ,Signal transduction ,Neuroscience - Abstract
SUMMARY Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action., Graphical Abstract, In brief Suzuki et al. examine the role of eEF2K and retinoic acid signaling pathways in synaptic plasticity and rapid antidepressant effects. Their study establishes a causal link between synaptic scaling and rapid antidepressant effects and proposes that this form of synaptic plasticity is a key synaptic substrate for rapid antidepressant action.
- Published
- 2021
36. A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action
- Author
-
Pei-Yi Lin, Ege T. Kavalali, Zhenzhong Ma, Lisa M. Monteggia, and Melissa Mahgoub
- Subjects
Dynamins ,Hippocampus ,Tropomyosin receptor kinase B ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Mice ,Neurotrophic factors ,Postsynaptic potential ,medicine ,Animals ,Humans ,Receptor, trkB ,Receptor ,CA1 Region, Hippocampal ,Neurons ,Brain-Derived Neurotrophic Factor ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,CA3 Region, Hippocampal ,Antidepressive Agents ,Endocytosis ,HEK293 Cells ,medicine.anatomical_structure ,nervous system ,Schaffer collateral ,Synapses ,Antidepressant ,Ketamine ,Neuroscience ,Signal Transduction - Abstract
SUMMARY Ketamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the antidepressant effects and underlying ketamine-induced synaptic potentiation in the hippocampus. Here, we delete BDNF or TrkB in presynaptic CA3 or postsynaptic CA1 regions of the Schaffer collateral pathway to investigate the rapid antidepressant action of ketamine. The deletion of Bdnf in CA3 or CA1 blocks the ketamine-induced synaptic potentiation. In contrast, ablation of TrkB only in postsynaptic CA1 eliminates the ketamine-induced synaptic potentiation. We confirm BDNF-TrkB signaling in CA1 is required for ketamine’s rapid behavioral action. Moreover, ketamine application elicits dynamin1-dependent TrkB activation and downstream signaling to trigger rapid synaptic effects. Taken together, these data demonstrate a requirement for BDNF-TrkB signaling in CA1 neurons in ketamine-induced synaptic potentiation and identify a specific synaptic locus in eliciting ketamine’s rapid antidepressant effects., Graphical Abstract, In brief Lin et al. report the essential role of BDNF signaling through postsynaptic TrkB at CA3-CA1 synapses in ketamine’s synaptic potentiation and rapid antidepressant action. These findings establish a strong correlation between TrkB-dependent potentiation at the CA1 synaptic locus and the antidepressant behavioral action of ketamine.
- Published
- 2021
37. A subthreshold synaptic mechanism regulating BDNF expression and resting synaptic strength
- Author
-
Baris Alten, Patricia M. Horvath, Lisa M. Monteggia, Ege T. Kavalali, and Natali L. Chanaday
- Subjects
Transcription, Genetic ,Rest ,Neurotransmission ,Inhibitory postsynaptic potential ,Article ,General Biochemistry, Genetics and Molecular Biology ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Calcium Signaling ,RNA, Messenger ,Neurotransmitter ,Calcium signaling ,Neurons ,Synaptic scaling ,Chemistry ,Brain-Derived Neurotrophic Factor ,Excitatory Postsynaptic Potentials ,Neural Inhibition ,Gene Expression Regulation ,Inhibitory Postsynaptic Potentials ,Synapses ,Synaptic plasticity ,Excitatory postsynaptic potential ,NMDA receptor ,Neuroscience - Abstract
SUMMARY Recent studies have demonstrated that protein translation can be regulated by spontaneous excitatory neurotransmission. However, the impact of spontaneous neurotransmitter release on gene transcription remains unclear. Here, we study the effects of the balance between inhibitory and excitatory spontaneous neurotransmission on brain-derived neurotrophic factor (BDNF) regulation and synaptic plasticity. Blockade of spontaneous inhibitory events leads to an increase in the transcription of Bdnf and Npas4 through altered synaptic calcium signaling, which can be blocked by antagonism of NMDA receptors (NMDARs) or L-type voltage-gated calcium channels (VGCCs). Transcription is bidirectionally altered by manipulating spontaneous inhibitory, but not excitatory, currents. Moreover, blocking spontaneous inhibitory events leads to multiplicative downscaling of excitatory synaptic strength in a manner that is dependent on both transcription and BDNF signaling. These results reveal a role for spontaneous inhibitory neurotransmission in BDNF signaling that sets excitatory synaptic strength at rest., In brief Horvath et al. study spontaneous neurotransmission to demonstrate a primary role for inhibition in gene transcription and synaptic plasticity. Inhibitory current through GABAARs, but not excitatory current through AMPARs, bi-directionally regulates transcription of Bdnf and Npas4 at rest. Control over transcription of Bdnf enables mIPSC-driven regulation of excitatory synaptic weight., Graphical abstract
- Published
- 2021
38. Impact of DNMT1 and DNMT3a forebrain knockout on depressive- and anxiety like behavior in mice
- Author
-
Michael J. Morris, Elisa S. Na, Anita E. Autry, and Lisa M. Monteggia
- Subjects
DNA (Cytosine-5-)-Methyltransferase 1 ,Male ,0301 basic medicine ,Elevated plus maze ,Mice, 129 Strain ,medicine.drug_class ,Cognitive Neuroscience ,Experimental and Cognitive Psychology ,Anxiety ,Biology ,Anxiolytic ,DNA methyltransferase ,Article ,DNA Methyltransferase 3A ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,Prosencephalon ,0302 clinical medicine ,medicine ,Animals ,DNA (Cytosine-5-)-Methyltransferases ,Gene knockout ,Prepulse inhibition ,Mice, Knockout ,Mice, Inbred BALB C ,Behavior, Animal ,Depression ,Prepulse Inhibition ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,embryonic structures ,DNA methylation ,Knockout mouse ,Forebrain ,Neuroscience ,030217 neurology & neurosurgery - Abstract
DNA methylation has been shown to impact certain forms of synaptic and behavioral plasticity that have been implicated in the development in psychiatric disorders. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes that continue to be expressed in postmitotic neurons in the forebrain. Using a conditional forebrain knockout of DNMT1 or DNMT3a we assessed the role of these DNMTs in anxiety and depressive-like behavior in mice using an array of behavioral testing paradigms. Forebrain deletion of DNMT1 had anxiolytic and antidepressant-like properties as assessed by elevated plus maze, novelty suppressed feeding, forced swim, and social interaction tests. DNMT3a knockout mice, by contrast, did not exhibit significant behavioral alterations in these tests. Given the putative role of altered DNA methylation patterns in the development of schizophrenia, we also assessed DNMT1 and DNMT3a knockout mice in a prepulse inhibition task and found an enhanced prepulse inhibition of startle in DNMT1 knockouts relative to wild type mice, with no change evident in DNMT3a knockout mice. Our data suggest that DNMT1 and DNMT3a are distinctly involved in affective behavior and that DNMT1 may ultimately represent a potential target for treatment of certain affective behavioral disorders.
- Published
- 2016
39. Spontaneous and evoked neurotransmission are partially segregated at inhibitory synapses
- Author
-
Patricia M. Horvath, Lisa M. Monteggia, Ege T. Kavalali, and Michelle K Piazza
- Subjects
QH301-705.5 ,Science ,Neurotransmission ,Hippocampal formation ,In Vitro Techniques ,Inhibitory postsynaptic potential ,Synaptic vesicle ,Hippocampus ,Synaptic Transmission ,General Biochemistry, Genetics and Molecular Biology ,GABA Antagonists ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Glutamatergic ,Animals ,Biology (General) ,GABAergic Neurons ,GABAergic neurotransmission ,Cells, Cultured ,General Immunology and Microbiology ,spontaneous release ,General Neuroscience ,Neural Inhibition ,General Medicine ,Receptors, GABA-A ,Electric Stimulation ,picrotoxin ,chemistry ,Inhibitory Postsynaptic Potentials ,Excitatory postsynaptic potential ,Medicine ,GABAergic ,Rat ,Female ,Neuroscience ,Picrotoxin ,Research Article - Abstract
Synaptic transmission is initiated via spontaneous or action-potential evoked fusion of synaptic vesicles. At excitatory synapses, glutamatergic receptors activated by spontaneous and evoked neurotransmission are segregated. Although inhibitory synapses also transmit signals spontaneously or in response to action potentials, they differ from excitatory synapses in both structure and function. Therefore, we hypothesized that inhibitory synapses may have different organizing principles. We report picrotoxin, a GABAAR antagonist, blocks neurotransmission in a use-dependent manner at rat hippocampal synapses and therefore can be used to interrogate synaptic properties. Using this tool, we uncovered partial segregation of inhibitory spontaneous and evoked neurotransmission. We found up to 40% of the evoked response is mediated through GABAARs which are only activated by evoked neurotransmission. These data indicate GABAergic spontaneous and evoked neurotransmission processes are partially non-overlapping, suggesting they may serve divergent roles in neuronal signaling.
- Published
- 2019
40. Increasing doses of ketamine curtail antidepressant responses and suppress associated synaptic signaling pathways
- Author
-
Ji-Woon Kim and Lisa M. Monteggia
- Subjects
Male ,Hippocampus ,Pharmacology ,Hippocampal formation ,Article ,03 medical and health sciences ,Behavioral Neuroscience ,Mice ,0302 clinical medicine ,Neurotrophic factors ,Medicine ,Animals ,Ketamine ,030304 developmental biology ,0303 health sciences ,Depressive Disorder, Major ,Neuronal Plasticity ,Behavior, Animal ,business.industry ,Brain-Derived Neurotrophic Factor ,Long-term potentiation ,Antidepressive Agents ,Mice, Inbred C57BL ,Disease Models, Animal ,Synaptic plasticity ,Antidepressant ,Synaptic signaling ,business ,030217 neurology & neurosurgery ,medicine.drug ,Signal Transduction - Abstract
Clinical findings show that a single subanesthetic dose of ketamine elicits rapid antidepressant effects. Accumulating data suggests that ketamine blocks the N-methyl-D-aspartate receptor and results in specific effects on intracellular signaling including increased brain-derived neurotrophic factor (BDNF) protein expression, which augments synaptic responses required for rapid antidepressant effects. To further investigate this potential mechanism for ketamine’s antidepressant action, we examined the effect of increasing ketamine doses on intracellular signaling, synaptic plasticity, and rapid antidepressant effects. Given that ketamine is often used at 2.5−10 mg/kg to examine antidepressant effects and 20−50 mg/kg to model schizophrenia, we compared effects at 5, 20 and 50 mg/kg. We found that intraperitoneal (i.p.) injection of low dose (5 mg/kg) ketamine produces rapid antidepressant effects, which were not observed at 20 or 50 mg/kg. At 5 mg/kg ketamine significantly increased the level of BDNF, a protein necessary for the rapid antidepressant effects, while 20 and 50 mg/kg ketamine did not alter BDNF levels in the hippocampus. Low concentration ketamine also evoked the highest synaptic potentiation in the hippocampal CA1, while higher concentrations significantly decreased the synaptic effects. Our results suggest low dose ketamine produces antidepressant effects and has independent behavioral and synaptic effects compared to higher doses of ketamine that are used to model schizophrenia. These findings strengthen our knowledge on specific signaling associated with ketamine’s rapid antidepressant effects.
- Published
- 2019
41. TrkB Signaling in Dorsal Raphe Nucleus is Essential for Antidepressant Efficacy and Normal Aggression Behavior
- Author
-
Megumi Adachi, Anita E. Autry, Kanzo Suzuki, Lisa M. Monteggia, and Melissa Mahgoub
- Subjects
Dorsal Raphe Nucleus ,Male ,0301 basic medicine ,Poison control ,Tropomyosin receptor kinase B ,Animals, Genetically Modified ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Dorsal raphe nucleus ,Limbic system ,Neurotrophic factors ,Neuroplasticity ,medicine ,Animals ,Receptor, trkB ,Pharmacology ,Behavior, Animal ,Depression ,Brain-Derived Neurotrophic Factor ,musculoskeletal, neural, and ocular physiology ,Antidepressive Agents ,Disease Models, Animal ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Antidepressant ,Original Article ,Psychopharmacology ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Brain-derived neurotrophic factor (BDNF) and its high affinity receptor, tropomyosin receptor kinase B (TrkB), have important roles in neural plasticity and are required for antidepressant efficacy. Studies examining the role of BDNF-TrkB signaling in depression and antidepressant efficacy have largely focused on the limbic system, leaving it unclear whether this signaling is important in other brain regions. BDNF and TrkB are both highly expressed in the dorsal raphe nucleus (DRN), a brain region that has been suggested to have a role in depression and antidepressant action, although it is unknown whether BDNF and TrkB in the dorsal raphe nucleus are involved in these processes. We combined the adeno-associated virus (AAV) with the Cre-loxP site-specific recombination system to selectively knock down either Bdnf or TrkB in the DRN. These mice were then characterized in several behavioral paradigms including measures of depression-related behavior and antidepressant efficacy. We show that knockdown of TrkB, but not Bdnf, in the DRN results in loss of antidepressant efficacy and increased aggression-related behavior. We also show that knockdown of TrkB or Bdnf in this brain region does not have an impact on weight, activity levels, anxiety, or depression-related behaviors. These data reveal a critical role for TrkB signaling in the DRN in mediating antidepressant responses and normal aggression behavior. The results also suggest a non-cell autonomous role for BDNF in the DRN in mediating antidepressant efficacy.
- Published
- 2016
42. Effects of a ketamine metabolite on synaptic NMDAR function
- Author
-
Kanzo Suzuki, Kevin W. Hunt, Elena Nosyreva, Lisa M. Monteggia, and Ege T. Kavalali
- Subjects
0301 basic medicine ,Multidisciplinary ,Hydroxynorketamine ,business.industry ,Metabolite ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Text mining ,chemistry ,Medicine ,NMDA receptor ,Ketamine ,business ,Neuroscience ,030217 neurology & neurosurgery ,Function (biology) ,medicine.drug - Published
- 2017
43. Meeting Report: Can We Make Animal Models of Human Mental Illness?
- Author
-
Eric J. Nestler, Hakon Heimer, and Lisa M. Monteggia
- Subjects
0301 basic medicine ,Consensus ,Models, Genetic ,Mental Disorders ,Disease ,Congresses as Topic ,Mental illness ,medicine.disease ,Behavioral or ,Article ,03 medical and health sciences ,Disease Models, Animal ,030104 developmental biology ,0302 clinical medicine ,medicine ,Animals ,Engineering ethics ,Nervous System Diseases ,Psychology ,030217 neurology & neurosurgery ,Biological Psychiatry ,Organ system ,Neuropsychiatric disease - Abstract
Modeling aspects of the human condition in animals has provided invaluable information on the physiology of all organ systems and has assisted in the development of virtually all new therapeutics. Research in cardiovascular disease, cancer, immunology, and other disciplines has benefited substantially from the availability of animal models that capture aspects of specific human diseases and that have been used effectively to advance new treatments. By comparison, animal models for neurological and psychiatric disorders have faced several unique obstacles. This paper highlights topics covered in a recent Cold Spring Harbor Laboratory meeting charged with examining the status of animal models for mental illness. The consensus of the conference is that despite the difficulties inherent with modeling brain disorders in animals, when used judiciously-fully cognizant that models of specific behavioral or biological aspects cannot completely recapitulate the human disorder-animal research is crucial for advancing our understanding of neuropsychiatric disease.
- Published
- 2018
44. Correction: D-cycloserine improves synaptic transmission in an animal mode of Rett syndrome
- Author
-
Héctor De Jesús-Cortés, Yasemin Onder, Elisa S. Na, Andrew A. Pieper, Vijayashree Ramesh, Arlene Martinez-Rivera, Zeeba D. Kabir, Anjali M. Rajadhyaksha, Lisa M. Monteggia, and Jieqi Wang
- Subjects
Male ,Apnea ,Methyl-CpG-Binding Protein 2 ,D-cycloserine ,lcsh:Medicine ,Rett syndrome ,Mice, Transgenic ,Neurotransmission ,Hippocampus ,Synaptic Transmission ,Mice ,Tremor ,medicine ,Rett Syndrome ,Animals ,Muscle Strength ,lcsh:Science ,Gait ,Multidisciplinary ,business.industry ,Brain-Derived Neurotrophic Factor ,lcsh:R ,Correction ,medicine.disease ,Corpus Striatum ,Disease Models, Animal ,Cycloserine ,lcsh:Q ,business ,Neuroscience ,Locomotion ,Brain Stem - Abstract
Rett syndrome (RTT), a leading cause of intellectual disability in girls, is predominantly caused by mutations in the X-linked gene MECP2. Disruption of Mecp2 in mice recapitulates major features of RTT, including neurobehavioral abnormalities, which can be reversed by re-expression of normal Mecp2. Thus, there is reason to believe that RTT could be amenable to therapeutic intervention throughout the lifespan of patients after the onset of symptoms. A common feature underlying neuropsychiatric disorders, including RTT, is altered synaptic function in the brain. Here, we show that Mecp2tm1.1Jae/y mice display lower presynaptic function as assessed by paired pulse ratio, as well as decreased long term potentiation (LTP) at hippocampal Schaffer-collateral-CA1 synapses. Treatment of Mecp2tm1.1Jae/y mice with D-cycloserine (DCS), an FDA-approved analog of the amino acid D-alanine with antibiotic and glycinergic activity, corrected the presynaptic but not LTP deficit without affecting deficient hippocampal BDNF levels. DCS treatment did, however, partially restore lower BDNF levels in the brain stem and striatum. Thus, treatment with DCS may mitigate the severity of some of the neurobehavioral symptoms experienced by patients with Rett syndrome.
- Published
- 2018
45. The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects
- Author
-
Lisa M. Monteggia and Ege T. Kavalali
- Subjects
0301 basic medicine ,Pharmacology ,Hydroxynorketamine ,Metabolite ,Hot Topics ,03 medical and health sciences ,Psychiatry and Mental health ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,medicine ,Antidepressant ,NMDA receptor ,Ketamine ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The Ketamine Metabolite 2R,6R-Hydroxynorketamine Blocks NMDA Receptors and Impacts Downstream Signaling Linked to Antidepressant Effects
- Published
- 2017
46. Methods for In Vivo Gene Manipulation
- Author
-
Lisa M. Monteggia and Wei Xu
- Abstract
Recent advances in mouse genetics have opened many new avenues of research in which to explore gene function in the brain, and contributions to the pathophysiology and treatment of psychiatric disorders. The use of the mouse to explore gene function has contributed a better understanding of the role of specific genes in the nervous system including their influence on neural circuits and complex behavior.This chapter explores current approaches to manipulate gene function in a mouse. Genetically modified mice allow for the investigation of a particular gene in vivo. The approaches discussed highlight recent advances to specifically overexpress or disrupt a specific gene of interest in the brain. We also highlight viral-mediated gene transfer approaches to allow for spatial and temporal control of gene function.
- Published
- 2017
47. MeCP2 as an Activator of Gene Expression
- Author
-
Patricia M. Horvath and Lisa M. Monteggia
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,Repressor ,Gene Expression ,Rett syndrome ,Biology ,Article ,MECP2 ,03 medical and health sciences ,0302 clinical medicine ,Neurodevelopmental disorder ,Gene expression ,mental disorders ,medicine ,Rett Syndrome ,Animals ,Humans ,Genetic Predisposition to Disease ,Gene ,Genetics ,Activator (genetics) ,General Neuroscience ,medicine.disease ,Phenotype ,nervous system diseases ,030104 developmental biology ,Mutation ,030217 neurology & neurosurgery - Abstract
Rett Syndrome is a neurodevelopmental disorder that primarily affects females and is caused by mutations in the methyl-CpG-binding-protein 2 (MeCP2) gene. Initially, MeCP2 had been shown to be a repressor of gene transcription. In their 2008 paper, Chahrour and colleagues (DOI: 10.1126/science.1153252) reported that MeCP2 could also function as a transcriptional activator.
- Published
- 2017
48. Dynamic methylation driven by neuronal activity in hippocampal neurons impacts complex behavior
- Author
-
Anita E. Autry, Megumi Adachi, and Lisa M. Monteggia
- Subjects
Genetics ,Ecology ,Epigenetics in learning and memory ,Hippocampus ,DNA Methyltransferase Inhibitor ,Biology ,Cell biology ,DNA demethylation ,Neurotrophic factors ,DNA methylation ,Gene expression ,Epigenetics ,Ecology, Evolution, Behavior and Systematics ,Biotechnology - Abstract
Epigenetic processes are well-known to play critical roles in learning and memory. Among epigenetic processes, accumulating data suggests that DNA methylation in particular is a critical determinant of learning and memory. In vitro data have suggested that DNA methyltransferase inhibitors can trigger DNA demethylation and subsequent gene expression of the brain-derived neurotrophic factor gene in an activity dependent manner. To examine if these processes occur in vivo, we chronically infused DNMT inhibitors into the hippocampus and examined the impact on behavior. We find that chronic DNMT inhibition in the hippocampus results in increased anxiety-related behavior and deficits in context-dependent fear conditioning accompanied by an increase in BDNF expression. Gene expression changes were blocked by pretreatment with the NMDA receptor antagonist AP5, suggesting that DNMT inhibition enhances gene expression in an activity-dependent manner and that, conversely, the behavior deficits and abnormal gene expression are facilitated by NMDA receptor activity. Open image in new window
- Published
- 2015
49. Selective role for DNMT3a in learning and memory
- Author
-
Lisa M. Monteggia, Michael J. Morris, Elisa S. Na, and Megumi Adachi
- Subjects
Methyltransferase ,Memory, Episodic ,Cognitive Neuroscience ,Conditioning, Classical ,Long-Term Potentiation ,Experimental and Cognitive Psychology ,Real-Time Polymerase Chain Reaction ,Hippocampus ,environment and public health ,Article ,DNA Methyltransferase 3A ,Behavioral Neuroscience ,Cytosine nucleotide ,Memory ,Animals ,Learning ,DNA (Cytosine-5-)-Methyltransferases ,Episodic memory ,Gene knockout ,Mice, Knockout ,Mice, Inbred BALB C ,Long-term potentiation ,Associative learning ,Mice, Inbred C57BL ,Repressor Proteins ,embryonic structures ,Synaptic plasticity ,Knockout mouse ,Psychology ,Neuroscience - Abstract
Methylation of cytosine nucleotides is governed by DNA methyltransferases (DNMTs) that establish de novo DNA methylation patterns in early embryonic development (e.g., DNMT3a and DNMT3b) or maintain those patterns on hemimethylated DNA in dividing cells (e.g., DNMT1). DNMTs continue to be expressed at high levels in mature neurons, however their impact on neuronal function and behavior are unclear. To address this issue we examined DNMT1 and DNMT3a expression following associative learning. We also generated forebrain specific conditional Dnmt1 or Dnmt3a knockout mice and characterized them in learning and memory paradigms as well as for alterations in long-term potentiation (LTP) and synaptic plasticity. Here, we report that experience in an associative learning task impacts expression of Dnmt3a, but not Dnmt1, in brain areas that mediate learning of this task. We also found that Dnmt3a knockout mice, and not Dnmt1 knockouts have synaptic alterations as well as learning deficits on several associative and episodic memory tasks. These findings indicate that the de novo DNA methylating enzyme DNMT3a in postmitotic neurons is necessary for normal memory formation and its function cannot be substituted by the maintenance DNA methylating enzyme DNMT1.
- Published
- 2014
50. Engineering MeCP2 to spy on its targets
- Author
-
Patricia M. Horvath and Lisa M. Monteggia
- Subjects
0301 basic medicine ,congenital, hereditary, and neonatal diseases and abnormalities ,Methyl-CpG-Binding Protein 2 ,Biotin ,Rett syndrome ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,MECP2 ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Gene expression ,medicine ,Rett Syndrome ,Animals ,Genetics ,food and beverages ,General Medicine ,medicine.disease ,Repressor Proteins ,030104 developmental biology ,chemistry ,METHYL-CpG-BINDING PROTEIN 2 ,Biotinylation ,030217 neurology & neurosurgery - Abstract
Mutations in MECP2 cause Rett syndrome (RTT), an X-linked neurological disorder characterized by regressive loss of neurodevelopmental milestones and acquired psychomotor deficits. However, the cellular heterogeneity of the brain impedes an understanding of how MECP2 mutations contribute to RTT. Here we developed a Cre-inducible method for cell type-specific biotin tagging of MeCP2 in mice. Combining this approach with an allelic series of knockin mice carrying frequent RTT mutations (T158M and R106W) enabled the selective profiling of RTT-associated nuclear transcriptomes in excitatory and inhibitory cortical neurons. We found that most gene expression changes are largely specific to each RTT mutation and cell type. Lowly expressed cell type-enriched genes are preferentially disrupted by MeCP2 mutations, with upregulated and downregulated genes reflecting distinct functional categories. Subcellular RNA analysis in MeCP2 mutant neurons further reveals reductions in the nascent transcription of long genes and uncovers widespread post-transcriptional compensation at the cellular level. Finally, we overcame X-linked cellular mosaicism in female RTT models and identified distinct gene expression changes between neighboring wild-type and mutant neurons, altogether providing contextual insights into RTT etiology that support personalized therapeutic interventions.
- Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.