3,780 results on '"Dendritic Spine"'
Search Results
2. Enriched environment rescues bisphenol A induced anxiety-like behavior and cognitive impairment by modulating synaptic plasticity
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Li, Jiong, Yu, Guangyin, Wang, Laijian, Zhang, Wenjun, Ke, Wenya, Li, Yifei, Liu, Danlei, Xie, Keman, Xu, Yuanyuan, Cha, Caihui, Guo, Guoqing, and Zhang, Jifeng
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- 2025
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3. Wireless optogenetic stimulation on the prelimbic to the nucleus accumbens core circuit attenuates cocaine-induced behavioral sensitization
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Ku, Min Jeong, Kim, Choong Yeon, Park, Jong Woo, Lee, Seohyeon, Jeong, Eun Young, Jeong, Jae-Woong, Kim, Wha Young, and Kim, Jeong-Hoon
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- 2024
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4. Manipulation of radixin phosphorylation in the nucleus accumbens core modulates risky choice behavior
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Kwak, Myung Ji, Choi, Su Jeong, Cai, Wen Ting, Cho, Bo Ram, Han, Joonyeup, Park, Jong Woo, Riecken, Lars Björn, Morrison, Helen, Choi, Se-Young, Kim, Wha Young, and Kim, Jeong-Hoon
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- 2024
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5. CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny
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Assendorp, Nora, Fossati, Matteo, Libé-Philippot, Baptiste, Christopoulou, Eirini, Depp, Marine, Rapone, Roberta, Dingli, Florent, Loew, Damarys, Vanderhaeghen, Pierre, and Charrier, Cécile
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- 2024
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6. Ubiquitin ligase RFWD2 promotes dendritic spine and synapse formation by activating the ERK/PEA3/c-Jun pathway in rat cerebral cortical neurons
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Zhong, Guangshang, Fang, Zhuling, Sun, Tingting, Ying, Mengjiao, Wang, Ao, Chen, Ying, Wang, Haojie, Ma, Caiyun, Wang, Chunjing, Ge, Rongjing, Liu, Gaofeng, and Guo, Yu
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- 2024
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7. Histological analysis of neuronal changes in the olfactory cortex during pregnancy
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Matsuda, Ken Ichi, Takahashi, Tomoki, Morishita, Sae, and Tanaka, Masaki
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- 2024
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8. Altered amantadine effects after repetitive treatment for l-dopa-induced involuntary movements in a rat model of Parkinson’s disease
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Murakami, Yoshiki, Nishijima, Haruo, Nakamura, Takashi, Furukawa, Tomonori, Kinoshita, Iku, Kon, Tomoya, Suzuki, Chieko, and Tomiyama, Masahiko
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- 2023
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9. The MCPH7 Gene Product STIL Is Essential for Dendritic Spine Formation.
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Matsuki, Tohru, Tabata, Hidenori, Ueda, Masashi, Ito, Hideaki, Nagata, Koh-ichi, Tsuneura, Yumi, Eda, Shima, Kasai, Kenji, and Nakayama, Atsuo
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GUANINE nucleotide exchange factors , *LONG-term potentiation , *CELL cycle proteins , *DENDRITIC spines , *SPINE , *NEURONS - Abstract
Dendritic spine formation/maintenance is highly dependent on actin cytoskeletal dynamics, which is regulated by small GTPases Rac1 and Cdc42 through their downstream p21-activated kinase/LIM-kinase-I/cofilin pathway. ARHGEF7, also known as ß-PIX, is a guanine nucleotide exchange factor for Rac1 and Cdc42, thereby activating Rac1/Cdc42 and the downstream pathway, leading to the upregulation of spine formation/maintenance. We found that STIL, one of the primary microcephaly gene products, is associated with ARHGEF7 in dendritic spines and that knockdown of Stil resulted in a significant reduction in dendritic spines in neurons both in vitro and in vivo. Rescue experiments indicated that the STIL requirement for spine formation/maintenance depended on its coiled coil domain that mediates the association with ARHGEF7. The overexpression of Rac1/Cdc42 compensated for the spine reduction caused by STIL knockdown. FRET experiments showed that Rac activation is impaired in STIL knockdown neurons. Chemical long-term potentiation, which triggers Rac activation, promoted STIL accumulation in the spine and its association with ARHGEF7. The dynamics of these proteins further supported their coordinated involvement in spine formation/maintenance. Based on these findings, we concluded that the centrosomal protein STIL is a novel regulatory factor essential for spine formation/maintenance by activating Rac and its downstream pathway, possibly through the association with ARHGEF7. [ABSTRACT FROM AUTHOR]
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- 2025
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10. A synapse-specific refractory period for plasticity at individual dendritic spines.
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Flores, Juan C., Sarkar, Dipannita, and Zito, Karen
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DENDRITIC spines , *NEUROPLASTICITY , *SCAFFOLD proteins , *SYNAPSES , *SIGNALS & signaling - Abstract
How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation fully restored CaMKII signaling but only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to preplasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels. [ABSTRACT FROM AUTHOR]
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- 2025
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11. Evaluation of dendrite morphology in Wistar and genetic absence epileptic rats.
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Yazi, Sevdenur, Sehirli, Umit S., Gulhan, Rezzan, Onat, Filiz, and Kirazli, Ozlem
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Objective: Genetic Absence Epilepsy Rat from Strasbourg (GAERS), a rodent model genetically predisposed to absence epilepsy, serves as an experimental tool to elucidate the neuronal mechanisms underlying human absence epilepsy. This study aimed to investigate the morphological features of dendrites and dendritic spines of pyramidal neurons in somatosensory cortex and hippocampus of Wistar and GAERS rats. Material and method: Adult male GAERS (n = 5) and control Wistar (n = 5) rats were sacrificed by transcardial perfusion and brains were removed. Brain tissues were processed by Golgi impregnation method using FD Rapid GolgiStain Kit. Coronal sections were obtained with a cryostat. Pyramidal neurons in layers V–VI of the somatosensory cortex and the CA1 region of the hippocampus were examined using a light microscope and Neurolucida 360 software. Dendrite nodes, dendrite segments (dendritic branching), dendrite terminations, total dendrite length, dendritic spine density, and dendritic spine types were analyzed. Results: Compared to Wistar, GAERS exhibited significantly higher numbers of nodes (p = 0.0053, p = 0.0047), segments (p = 0.0036, p = 0.0036), and terminations (p = 0.0033, p = 0.0029) in the dendrites of the somatosensory cortex and the hippocampus, respectively. Furthermore, the total dendrite length (µm) (p = 0.0002, p = 0.0007) and the density of dendritic spines (1/µm) (p = 0.0168, p = 0.0120) were significantly high in GAERS compared to Wistar. When dendritic spine types were evaluated separately, stubby-type dendritic spines in the hippocampus were higher in GAERS compared to Wistar (p = 0.0045). Conclusion: Intense synaptic connections in the somatosensory cortex and the hippocampus of genetic absence epileptic rats led to morphological alterations in the dendrites and the dendritic spines of pyramidal neurons in these regions, potentially contributing to the pathophysiology of absence seizures. [ABSTRACT FROM AUTHOR]
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- 2025
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12. Hippocampal dendritic spines store-operated calcium entry and endoplasmic reticulum content is dynamic microtubule dependent
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Anastasiya Rakovskaya, Ekaterina Volkova, Ilya Bezprozvanny, and Ekaterina Pchitskaya
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Dendritic spine ,Spine apparatus ,Endoplasmic reticulum ,Store-operated calcium entry ,End-binding proteins ,Dynamic microtubules ,Medicine ,Science - Abstract
Abstract One of the mechanisms of calcium signalling in neurons is store-operated calcium entry (SOCE), which is activated when the calcium concentration in the smooth endoplasmic reticulum (ER) decreases and its protein-calcium sensor STIM (stromal interacting molecule) relocate to the endoplasmic reticulum and plasma membrane junctions, forms clusters and induces calcium entry. In electrically non-excitable cells, STIM1 is coupled with the positive end of a tubulin microtubule through interaction with EB1 (end-binding) protein, which controls its oligomerization, SOCE and participates in ER movement. STIM2 homologue, which is specific for mature hippocampal dendritic spines, is known to interact with EB3 protein, however, not much is known about the role of this interaction in STIM2 clustering or ER trafficking in neurons. Intriguingly, in neurons, reducing the expression of EB3 protein or disrupting the interaction of STIM2 protein with EB proteins results in decreased SOCE, in contrast to experiments with STIM1 in non-excitable cells. In this study, these two homologues are compared side-by-side in HEK-293T, and it is shown for the first time that their clustering and SOCE is oppositely regulated by dynamic tubulin microtubules. In particular, for STIM2, the interaction with dynamic microtubule cytoskeleton is required for clustering and is shown to potentiate SOCE, while for STIM1 this interaction restricts clustering, resulting in SOCE decrease. After store depletion in primary hippocampal neurons, the wild type STIM2 is redistributed from the necks to the heads of dendritic spines, while the STIM2 variant with a mutation that disrupts the interaction with EB proteins is excluded from dendritic spines. In addition, overexpression of the mutant variant leads to ER reorganization in neuronal soma and reduction of ER presence in spines. It also leads to a reduction in the number of spines containing the spine apparatus formed by ER cisternae, as well as a reduction in dendritic spines SOCE. These effects are opposite of those detected during overexpression of the wild type STIM2. Considered together, these findings underline the important role of dynamic microtubules in regulation of neuronal SOCE and ER morphology.
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- 2025
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13. Cell-autonomous reduction of CYFIP2 changes dendrite length, dendritic protrusion morphology, and inhibitory synapse density in the hippocampal CA1 pyramidal neurons of 17-month-old mice
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Yoonhee Kim, Ruiying Ma, Yinhua Zhang, Hyae Rim Kang, U Suk Kim, and Kihoon Han
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CYFIP2 ,CA1 pyramidal neuron ,dendrite ,dendritic spine ,synapse ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The cytoplasmic FMR1-interacting protein 2 (CYFIP2) have diverse molecular functions in neurons, including the regulation of actin polymerization, mRNA translation, and mitochondrial morphology and function. Mutations in the CYFIP2 gene are associated with early-onset epilepsy and neurodevelopmental disorders, while decreases in its protein levels are linked to Alzheimer's disease (AD). Notably, previous research has revealed AD-like phenotypes, such as dendritic spine loss, in the hippocampal CA1 pyramidal neurons of 12-month-old Cyfip2 heterozygous mice but not of age-matched CA1 pyramidal neuron-specific Cyfip2 conditional knock-out (cKO) mice. This study aims to investigate whether dendritic spine loss in Cyfip2 cKO mice is merely delayed compared to Cyfip2 heterozygous mice, and to explore further neuronal phenotypes regulated by CYFIP2 in aged mice. We characterized dendrite and dendritic protrusion morphologies, along with excitatory/inhibitory synapse densities in CA1 pyramidal neurons of 17-month-old Cyfip2 cKO mice. Overall dendritic branching was normal, with a reduction in the length of basal, not apical, dendrites in CA1 pyramidal neurons of Cyfip2 cKO mice. Furthermore, while dendritic protrusion density remained normal, alterations were observed in the length of mushroom spines and the head volume of stubby spines in basal, not apical, dendrites of Cyfip2 cKO mice. Although excitatory synapse density remained unchanged, inhibitory synapse density increased in apical, not basal, dendrites of Cyfip2 cKO mice. Consequently, a cell-autonomous reduction of CYFIP2 appears insufficient to induce dendritic spine loss in CA1 pyramidal neurons of aged mice. However, CYFIP2 is required to maintain normal dendritic length, dendritic protrusion morphology, and inhibitory synapse density.
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- 2024
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14. The Role of Acid-Sensing Ion Channel 1A (ASIC1A) in the Behavioral and Synaptic Effects of Oxycodone and Other Opioids.
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Fuller, Margaret J., Andrys, Noah R. R., Gupta, Subhash C., Ghobbeh, Ali, Kreple, Collin J., Fan, Rong, Taugher-Hebl, Rebecca J., Radley, Jason J., Lalumiere, Ryan T., and Wemmie, John A.
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ACID-sensing ion channels , *OPIOID abuse , *COCAINE-induced disorders , *DENDRITIC spines , *METHYL aspartate - Abstract
Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies. [ABSTRACT FROM AUTHOR]
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- 2024
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15. Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders.
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Barrantes, Francisco J.
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COGNITION disorder risk factors ,ALZHEIMER'S disease ,FUNCTIONAL connectivity ,NEURONS ,NEURAL pathways ,NEUROPHYSIOLOGY ,NEUROPLASTICITY ,NEURAL transmission ,AGE distribution ,NEURODEGENERATION ,POSITRON emission tomography ,COGNITION disorders ,DEMENTIA ,HIPPOCAMPUS (Brain) ,MICROSCOPY ,COGNITION ,COGNITIVE aging ,GENETICS ,MEMORY disorders ,NEUROTRANSMITTER receptors ,BIOMARKERS ,ACTIVE aging - Abstract
Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, the family, and society at large. Cognitive pathologies are driven by a multiplicity of factors, from genetic mutations and genetic risk factors, neurotransmitter-associated dysfunction, abnormal connectomics at the level of local neuronal circuits and broader brain networks, to environmental influences able to modulate some of the endogenous factors. Otherwise healthy older adults can be expected to experience some degree of mild cognitive impairment, some of which fall into the category of subjective cognitive deficits in clinical practice, while many neurodevelopmental and neurodegenerative diseases course with more profound alterations of cognition, particularly within the spectrum of the dementias. Our knowledge of the underlying neuropathological mechanisms at the root of this ample palette of clinical entities is far from complete. This review looks at current knowledge on synaptic modifications in the context of cognitive function along healthy ageing and cognitive dysfunction in disease, providing insight into differential diagnostic elements in the wide range of synapse alterations, from those associated with the mild cognitive changes of physiological senescence to the more profound abnormalities occurring at advanced clinical stages of dementia. I propose the term "cognitive synaptopathy" to encompass the wide spectrum of synaptic pathologies associated with higher brain function disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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16. PAK1 inhibition with Romidepsin attenuates H‐reflex hyperexcitability after spinal cord injury.
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Kauer, Sierra D., Benson, Curtis A., Carrara, Jennifer M., Tarafder, Afrin A., Ibrahim, Youssef H., Estacion, Maile A., Waxman, Stephen G., and Tan, Andrew M.
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AUTONOMIC dysreflexia , *AUTONOMIC nervous system , *SPASTICITY , *MULTIPLE sclerosis , *STROKE , *SPINAL cord injuries - Abstract
Hyperreflexia associated with spasticity is a prevalent neurological condition characterized by excessive and exaggerated reflex responses to stimuli. Hyperreflexia can be caused by several diseases including multiple sclerosis, stroke and spinal cord injury (SCI). Although we have previously identified the contribution of the RAC1‐PAK1 pathway underlying spinal hyperreflexia with SCI‐induced spasticity, a feasible druggable target has not been validated. To assess the utility of targeting PAK1 to attenuate H‐reflex hyperexcitability, we administered Romidepsin, a clinically available PAK1 inhibitor, in Thy1‐YFP reporter mice. We performed longitudinal EMG studies with a study design that allowed us to assess pathological H‐reflex changes and drug intervention effects over time, before and after contusive SCI. As expected, our results show a significant loss of rate‐dependent depression – an indication of hyperreflexia and spasticity – 1 month following SCI as compared with baseline, uninjured controls (or before injury). Romidepsin treatment reduced signs of hyperreflexia in comparison with control cohorts and in pre‐ and post‐drug intervention in SCI animals. Neuroanatomical study further confirmed drug response, as romidepsin treatment also reduced the presence of SCI‐induced dendritic spine dysgenesis on α‐motor neurons. Taken together, our findings extend previous work demonstrating the utility of targeting PAK1 activity in SCI‐induced spasticity and support the novel use of romidepsin as an effective tool for managing spasticity. Key points: PAK1 plays a role in contributing to the development of spinal cord injury (SCI)‐induced spasticity by contributing to dendritic spine dysgenesis.In this study, we explored the preclinical utility of inhibiting PAK1 to reduce spasticity and dendritic spine dysgenesis in an SCI mouse model.Romidepsin is a PAK1 inhibitor approved in the US in 2009 for the treatment of cutaneous T‐cell lymphoma.Here we show that romidepsin treatment after SCI reduced SCI‐induced H‐reflex hyperexcitability and abnormal α‐motor neuron spine morphology.This study provides compelling evidence that romidepsin may be a promising therapeutic approach for attenuating SCI‐induced spasticity. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Reducing Filamin A Restores Cortical Synaptic Connectivity and Early Social Communication Following Cellular Mosaicism in Autism Spectrum Disorder Pathways.
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Binder, Matthew S., Escobar, Iris, Youfen Xu, Sokolov, Aidan M., Longbo Zhang, and Bordey, Angélique
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PYRAMIDAL neurons , *AUTISM spectrum disorders , *MOSAICISM , *DENDRITES , *PROTEIN crosslinking , *DENDRITIC spines - Abstract
Communication in the form of nonverbal, social vocalization, or crying is evolutionary conserved in mammals and is impaired early in human infants that are later diagnosed with autism spectrum disorder (ASD). Defects in infant vocalization have been proposed as an early sign of ASD that may exacerbate ASD development. However, the neural mechanisms associated with early communicative deficits in ASD are not known. Here, we expressed a constitutively active mutant of Rheb (RhebS16H), which is known to upregulate two ASD core pathways, mTOR complex 1 (mTORC1) and ERK1/2, in Layer (L) 2/3 pyramidal neurons of the neocortex of mice of either sex. We found that cellular mosaic expression of RhebS16H in L2/3 pyramidal neurons altered the production of isolation calls from neonatal mice. This was accompanied by an expected misplacement of neurons and dendrite overgrowth, along with an unexpected increase in spine density and length, which was associated with increased excitatory synaptic activity. This contrasted with the known decrease in spine density in RhebS16H neurons of 1-month-old mice. Reducing the levels of the actin cross-linking and adaptor protein filamin A (FLNA), known to be increased downstream of ERK1/2, attenuated dendrite overgrowth and fully restored spine properties, synaptic connectivity, and the production of pup isolation calls. These findings suggest that upper-layer cortical pyramidal neurons contribute to communicative deficits in a condition known to affect two core ASD pathways and that these mechanisms are regulated by FLNA. [ABSTRACT FROM AUTHOR]
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- 2024
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18. Development of an in vitro compound screening system that replicate the in vivo spine phenotype of idiopathic ASD model mice.
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Kazuma Maeda, Miki Tanimura, Yusaku Masago, Tsukasa Horiyama, Hiroshi Takemoto, Takuya Sasaki, Ryuta Koyama, Yuji Ikegaya, and Koichi Ogawa
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DRUG discovery ,SEROTONIN receptors ,CHEMICAL libraries ,AUTISM spectrum disorders ,SPINE abnormalities - Abstract
Autism Spectrum Disorder (ASD) is a developmental condition characterized by core symptoms including social difficulties, repetitive behaviors, and sensory abnormalities. Aberrant morphology of dendritic spines within the cortex has been documented in genetic disorders associated with ASD and ASD-like traits. We hypothesized that compounds that ameliorate abnormalities in spine dynamics might have the potential to ameliorate core symptoms of ASD. Because the morphology of the spine is influenced by signal inputs from other neurons and various molecular interactions, conventional singlemolecule targeted drug discovery methods may not suffice in identifying compounds capable of ameliorating spine morphology abnormalities. In this study, we focused on spine phenotypes in the cortex using BTBR T+ Itpr3tf/J (BTBR) mice, which have been used as a model for idiopathic ASD in various studies. We established an in vitro compound screening system using primary cultured neurons from BTBR mice to faithfully represent the spine phenotype. The compound library mainly comprised substances with known target molecules and established safety profiles, including those approved or validated through human safety studies. Following screening of this specialized library containing 181 compounds, we identified 15 confirmed hit compounds. The molecular targets of these hit compounds were largely focused on the 5-hydroxytryptamine receptor (5-HTR). Furthermore, both 5-HT1AR agonist and 5-HT3R antagonist were common functional profiles in hit compounds. Vortioxetine, possessing dual attributes as a 5-HT1AR agonist and 5-HT3R antagonist, was administered to BTBR mice once daily for a period of 7 days. This intervention not only ameliorated their spine phenotype but also alleviated their social behavior abnormality. These results of vortioxetine supports the usefulness of a spine phenotype-based assay system as a potent drug discovery platform targeting ASD core symptoms. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Amyloid-β Causes NMDA Receptor Dysfunction and Dendritic Spine Loss through mGluR1 and AKAP150-Anchored Calcineurin Signaling.
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Prikhodko, Olga, Freund, Ronald K., Sullivan, Emily, Kennedy, Matthew J., and Dell'Acqua, Mark L.
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DENDRITIC spines , *GLUTAMATE receptors , *SCAFFOLD proteins , *PHOSPHOPROTEIN phosphatases , *METHYL aspartate receptors - Abstract
Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca2+ influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca2+-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca2+-dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-β (Aβ) may impair learning and memory through biasing NMDAR Ca2+ signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP–CaN–LTD signaling was required for Aβ-mediated impairment of NMDAR synaptic Ca2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aβ acutely engages AKAP–CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca2+ influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aβ-mediated synaptic dysfunction. [ABSTRACT FROM AUTHOR]
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- 2024
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20. Treadmill Exercise Reshapes Cortical Astrocytic and Neuronal Activity to Improve Motor Learning Deficits Under Chronic Alcohol Exposure.
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Liu, Linglin, Luo, Lanzhi, Wei, Ji-an, Xu, Xintong, So, Kwok-Fai, and Zhang, Li
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Alcohol abuse induces various neurological disorders including motor learning deficits, possibly by affecting neuronal and astrocytic activity. Physical exercise is one effective approach to remediate synaptic loss and motor deficits as shown by our previous works. In this study, we unrevealed the role of exercise training in the recovery of cortical neuronal and astrocytic functions. Using a chronic alcohol injection mouse model, we found the hyperreactivity of astrocytes along with dendritic spine loss plus lower neuronal activity in the primary motor cortex. Persistent treadmill exercise training, on the other hand, improved neural spine formation and inhibited reactive astrocytes, alleviating motor learning deficits induced by alcohol exposure. These data collectively support the potency of endurance exercise in the rehabilitation of motor functions under alcohol abuse. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Sex dierences in motor learning flexibility are accompanied by sex dierences in mushroom spine pruning of the mouse primary motor cortex during adolescenc.
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Tekin, Michael, Hui Shen, and Smith, Sheryl S.
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MOTOR learning ,MOTOR cortex ,SPINE ,PYRAMIDAL neurons ,MUSHROOMS - Abstract
Background: Although males excel at motor tasks requiring strength, females exhibit greater motor learning flexibility. Cognitive flexibility is associated with low baseline mushroom spine densities achieved by pruning which can be triggered by α4βδ GABAA receptors (GABARs); defective synaptic pruning impairs this process. Methods: We investigated sex differences in adolescent pruning of mushroom spine pruning of layer 5 pyramidal cells of primary motor cortex (L5M1), a site essential for motor learning, using microscopic evaluation of Golgi stained sections. We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4βδ GABARs). We then compared performance of groups with different post-pubertal mushroom spine densities on motor learning (constant speed) and learning flexibility (accelerating speed following constant speed) rotarod tasks. Results: Mushroom spines in proximal L5M1 of female mice decreased >60% from PND35 (puberty onset) to PND56 (Pubertal: 2.23 ± 0.21 spines/10 μm; post-pubertal: 0.81 ± 0.14 spines/10 μm, P < 0.001); male mushroom spine density was unchanged. This was due to greater α4βδ GABAR expression in the female (P < 0.0001) because α4 -/- mice did not exhibit mushroom spine pruning. Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility. Conclusions: These results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Maintenance of Lognormal‐Like Skewed Dendritic Spine Size Distributions in Dentate Granule Cells of TNF, TNF‐R1, TNF‐R2, and TNF‐R1/2‐Deficient Mice.
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Rößler, Nina, Smilovic, Dinko, Vuksic, Mario, Jedlicka, Peter, and Deller, Thomas
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Dendritic spines are sites of synaptic plasticity and their head size correlates with the strength of the corresponding synapse. We recently showed that the distribution of spine head sizes follows a lognormal‐like distribution even after blockage of activity or plasticity induction. As the cytokine tumor necrosis factor (TNF) influences synaptic transmission and constitutive TNF and receptor (TNF‐R)‐deficiencies cause changes in spine head size distributions, we tested whether these genetic alterations disrupt the lognormality of spine head sizes. Furthermore, we distinguished between spines containing the actin‐modulating protein synaptopodin (SP‐positive), which is present in large, strong and stable spines and those lacking it (SP‐negative). Our analysis revealed that neither TNF‐deficiency nor the absence of TNF‐R1, TNF‐R2 or TNF‐R 1 and 2 (TNF‐R1/R2) degrades the general lognormal‐like, skewed distribution of spine head sizes (all spines, SP‐positive spines, SP‐negative spines). However, TNF, TNF‐R1 and TNF‐R2‐deficiency affected the width of the lognormal distribution, and TNF‐R1/2‐deficiency shifted the distribution to the left. Our findings demonstrate the robustness of the lognormal‐like, skewed distribution, which is maintained even in the face of genetic manipulations that alter the distribution of spine head sizes. Our observations are in line with homeostatic adaptation mechanisms of neurons regulating the distribution of spines and their head sizes. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Methionine oxidation of actin cytoskeleton attenuates traumatic memory retention via reactivating dendritic spine morphogenesis
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Cun-Dong Huang, Yu Shi, Fang Wang, Peng-Fei Wu, and Jian-Guo Chen
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Cued fear conditioning ,Actin cytoskeleton ,Dendritic spine ,Basolateral amygdala ,Molecule interacting with CasL 1 ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Post-traumatic stress disorder (PTSD) is characterized by hypermnesia of the trauma and a persistent fear response. The molecular mechanisms underlying the retention of traumatic memories remain largely unknown, which hinders the development of more effective treatments. Utilizing auditory fear conditioning, we demonstrate that a redox-dependent dynamic pathway for dendritic spine morphogenesis in the basolateral amygdala (BLA) is crucial for traumatic memory retention. Exposure to a fear-induced event markedly increased the reduction of oxidized filamentous actin (F-actin) and decreased the expression of the molecule interacting with CasL 1 (MICAL1), a methionine-oxidizing enzyme that directly oxidizes and depolymerizes F-actin, leading to cytoskeletal dynamic abnormalities in the BLA, which impairs dendritic spine morphogenesis and contributes to the persistence of fearful memories. Following fear conditioning, overexpression of MICAL1 in the BLA inhibited freezing behavior during fear memory retrieval via reactivating cytokinesis, whereas overexpression of methionine sulfoxide reductase B 1, a key enzyme that reduces oxidized F-actin monomer, increased freezing behavior during retrieval. Notably, intra-BLA injection of semaphorin 3A, an endogenous activator of MICAL1, rapidly disrupted fear memory within a short time window after conditioning. Collectively, our results indicate that redox modulation of actin cytoskeleton in the BLA is functionally linked to fear memory retention and PTSD-like memory.
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- 2024
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24. Cognitive synaptopathy: synaptic and dendritic spine dysfunction in age-related cognitive disorders
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Francisco J. Barrantes
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cognition ,cognitive impairment ,synapse ,dendritic spine ,memory ,ageing ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Cognitive impairment is a leading component of several neurodegenerative and neurodevelopmental diseases, profoundly impacting on the individual, the family, and society at large. Cognitive pathologies are driven by a multiplicity of factors, from genetic mutations and genetic risk factors, neurotransmitter-associated dysfunction, abnormal connectomics at the level of local neuronal circuits and broader brain networks, to environmental influences able to modulate some of the endogenous factors. Otherwise healthy older adults can be expected to experience some degree of mild cognitive impairment, some of which fall into the category of subjective cognitive deficits in clinical practice, while many neurodevelopmental and neurodegenerative diseases course with more profound alterations of cognition, particularly within the spectrum of the dementias. Our knowledge of the underlying neuropathological mechanisms at the root of this ample palette of clinical entities is far from complete. This review looks at current knowledge on synaptic modifications in the context of cognitive function along healthy ageing and cognitive dysfunction in disease, providing insight into differential diagnostic elements in the wide range of synapse alterations, from those associated with the mild cognitive changes of physiological senescence to the more profound abnormalities occurring at advanced clinical stages of dementia. I propose the term “cognitive synaptopathy” to encompass the wide spectrum of synaptic pathologies associated with higher brain function disorders.
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- 2024
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25. Spot Spine, a freely available ImageJ plugin for 3D detection and morphological analysis of dendritic spines [version 2; peer review: 1 approved, 3 approved with reservations]
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Nicolas Heck, Thomas Boudier, Tiago Ferreira, Philippe Mailly, and Jean-Francois Gilles
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Dendritic spine ,neuronal morphology ,neuroanatomy ,synapse ,image analysis ,ImageJ ,eng ,Medicine ,Science - Abstract
Background Dendritic spines are tiny protrusions found along the dendrites of neurons, and their number is a measure of the density of synaptic connections. Altered density and morphology is observed in several pathologies, and spine formation as well as morphological changes correlate with learning and memory. The detection of spines in microscopy images and the analysis of their morphology is therefore a prerequisite for many studies. We have developed a new open-source, freely available, plugin for ImageJ/FIJI, called Spot Spine, that allows detection and morphological measurements of spines in three dimensional images. Method Local maxima are detected in spine heads, and the intensity distribution around the local maximum is computed to perform the segmentation of each spine head. Spine necks are then traced from the spine head to the dendrite. Several parameters can be set to optimize detection and segmentation, and manual correction gives further control over the result of the process. Results The plugin allows the analysis of images of dendrites obtained with various labeling and imaging methods. Quantitative measurements are retrieved including spine head volume and surface, and neck length. Conclusion The plugin and instructions for use are available at https://imagej.net/plugins/spot-spine.
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- 2024
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26. Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain
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Yidan Tang, Jiahui Wu, Changliang Liu, Lu Gan, Hai Chen, Ya-Lan Sun, Jin Liu, Yuan-Xiang Tao, Tao Zhu, and Chan Chen
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Memory impairment ,Chronic neuropathic pain ,Extracellular vesicles ,microRNA ,Dendritic spine ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. Methods We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. Results The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. Conclusion Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP.
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- 2024
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27. Enhanced Spine Stability and Survival Lead to Increases in Dendritic Spine Density as an Early Response to Local Alpha-Synuclein Overexpression in Mouse Prefrontal Cortex
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Bosch, Peter J., Kerr, Gemma, Cole, Rachel, Warwick, Charles A., Wendt, Linder H., Pradeep, Akash, Bagnall, Emma, and Aldridge, Georgina M.
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- 2024
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28. Evidence that Alzheimer's Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry.
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Huang, Zhen
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- *
ALZHEIMER'S disease , *NEUROPLASTICITY , *GENE regulatory networks , *APOLIPOPROTEIN E , *OLIGOMERS , *SYNAPSES - Abstract
Mounting evidence indicates that a physiological function of amyloid-β (Aβ) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between Aβ and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in Aβ-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer's disease (AD). Specifically, I discuss evidence that Aβ and ApoE, two crucial players in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric Aβ and inhibiting its assembly into toxic oligomers. Conversely, Aβ oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of "eat-me" signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to Aβ-orchestrated plasticity, in which sleep is not only induced by Aβ but is also required for Aβ-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Biophysical Modeling of Synaptic Plasticity.
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Lee, Christopher T., Bell, Miriam, Bonilla-Quintana, Mayte, and Rangamani, Padmini
- Abstract
Dendritic spines are small, bulbous compartments that function as postsynaptic sites and undergo intense biochemical and biophysical activity. The role of the myriad signaling pathways that are implicated in synaptic plasticity is well studied. A recent abundance of quantitative experimental data has made the events associated with synaptic plasticity amenable to quantitative biophysical modeling. Spines are also fascinating biophysical computational units because spine geometry, signal transduction, and mechanics work in a complex feedback loop to tune synaptic plasticity. In this sense, ideas from modeling cell motility can inspire us to develop multiscale approaches for predictive modeling of synaptic plasticity. In this article, we review the key steps in postsynaptic plasticity with a specific focus on the impact of spine geometry on signaling, cytoskeleton rearrangement, and membrane mechanics. We summarize the main experimental observations and highlight how theory and computation can aid our understanding of these complex processes. [ABSTRACT FROM AUTHOR]
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- 2024
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30. PCDH17 restricts dendritic spine morphogenesis by regulating ROCK2-dependent control of the actin cytoskeleton, modulating emotional behavior.
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Laidong Yu, Fangfang Zeng, Mengshu Fan, Kexuan Zhang, Jingjing Duan, Yalu Tan, Panlin Liao, Jin Wen, Chenyu Wang, Meilin Wang, Jialong Yuan, Xinxin Pang, Yan Huang, Yangzhou Zhang, Jia-Da Li, Zhuohua Zhang, and Zhonghua Hu
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DENDRITIC spines ,CYTOSKELETON ,AFFECTIVE disorders ,SYNAPTOGENESIS ,NEUROBEHAVIORAL disorders ,F-actin - Abstract
Proper regulation of synapse formation and elimination is critical for establishing mature neuronal circuits and maintaining brain function. Synaptic abnormalities, such as defects in the density and morphology of postsynaptic dendritic spines, underlie the pathology of various neuropsychiatric disorders. Protocadherin 17 (PCDH17) is associated with major mood disorders, including bipolar disorder and depression. However, the molecular mechanisms by which PCDH17 regulates spine number, morphology, and behavior remain elusive. In this study, we found that PCDH17 functions at postsynaptic sites, restricting the number and size of dendritic spines in excitatory neurons. Selective overexpression of PCDH17 in the ventral hippocampal CA1 results in spine loss and anxiety- and depression-like behaviors in mice. Mechanistically, PCDH17 interacts with actin-relevant proteins and regulates actin filament (F-actin) organization. Specifically, PCDH17 binds to ROCK2, increasing its expression and subsequently enhancing the activity of downstream targets such as LIMK1 and the phosphorylation of cofilin serine-3 (Ser3). Inhibition of ROCK2 activity with belumosudil (KD025) ameliorates the defective F-actin organization and spine structure induced by PCDH17 overexpression, suggesting that ROCK2 mediates the effects of PCDH17 on F-actin content and spine development. Hence, these findings reveal a novel mechanism by which PCDH17 regulates synapse development and behavior, providing pathological insights into the neurobiological basis of mood disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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31. Schizophrenia risk proteins ZNF804A and NT5C2 interact in cortical neurons.
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Aabdien, Afra, Sichlinger, Laura, Borgel, Zoe, Jones, Madeleine R., Waston, Iain A., Gatford, Nicholas J. F., Raval, Pooja, Tanangonan, Lloyd, Powell, Timothy R., Duarte, Rodrigo R. R., and Srivastava, Deepak P.
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- *
ZINC-finger proteins , *DENDRITIC spines , *GENOME-wide association studies , *NEURONS , *SCHIZOPHRENIA , *PROGENITOR cells - Abstract
The zinc finger protein 804A (ZNF804A) and the 5′‐nucleotidase cytosolic II (NT5C2) genes are amongst the first schizophrenia susceptibility genes to have been identified in large‐scale genome‐wide association studies. ZNF804A has been implicated in the regulation of neuronal morphology and is required for activity‐dependent changes to dendritic spines. Conversely, NT5C2 has been shown to regulate 5′ adenosine monophosphate‐activated protein kinase activity and has been implicated in protein synthesis in human neural progenitor cells. Schizophrenia risk genotype is associated with reduced levels of both NT5C2 and ZNF804A in the developing brain, and a yeast two‐hybrid screening suggests that their encoded proteins physically interact. However, it remains unknown whether this interaction also occurs in cortical neurons and whether they could jointly regulate neuronal function. Here, we show that ZNF804A and NT5C2 colocalise and interact in HEK293T cells and that their rodent homologues, ZFP804A and NT5C2, colocalise and form a protein complex in cortical neurons. Knockdown of the Zfp804a or Nt5c2 genes resulted in a redistribution of both proteins, suggesting that both proteins influence the subcellular targeting of each other. The identified interaction between ZNF804A/ZFP804A and NT5C2 suggests a shared biological pathway pertinent to schizophrenia susceptibility within a neuronal cell type thought to be central to the neurobiology of the disorder, providing a better understanding of its genetic landscape. [ABSTRACT FROM AUTHOR]
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- 2024
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32. Schwann cell-derived extracellular vesicles promote memory impairment associated with chronic neuropathic pain.
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Tang, Yidan, Wu, Jiahui, Liu, Changliang, Gan, Lu, Chen, Hai, Sun, Ya-Lan, Liu, Jin, Tao, Yuan-Xiang, Zhu, Tao, and Chen, Chan
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SCIATIC nerve injuries ,MEMORY disorders ,EXTRACELLULAR vesicles ,NEURALGIA ,CHRONIC pain ,DEUBIQUITINATING enzymes ,DRUG-seeking behavior - Abstract
Background: The pathogenesis of memory impairment, a common complication of chronic neuropathic pain (CNP), has not been fully elucidated. Schwann cell (SC)-derived extracellular vesicles (EVs) contribute to remote organ injury. Here, we showed that SC-EVs may mediate pathological communication between SCs and hippocampal neurons in the context of CNP. Methods: We used an adeno-associated virus harboring the SC-specific promoter Mpz and expressing the CD63-GFP gene to track SC-EVs transport. microRNA (miRNA) expression profiles of EVs and gain-of-function and loss-of-function regulatory experiments revealed that miR-142-5p was the main cargo of SC-EVs. Next, luciferase reporter gene and phenotyping experiments confirmed the direct targets of miR-142-5p. Results: The contents and granule sizes of plasma EVs were significantly greater in rats with chronic sciatic nerve constriction injury (CCI)than in sham rats. Administration of the EV biogenesis inhibitor GW4869 ameliorated memory impairment in CCI rats and reversed CCI-associated dendritic spine damage. Notably, during CCI stress, SC-EVs could be transferred into the brain through the circulation and accumulate in the hippocampal CA1-CA3 regions. miR-142-5p was the main cargo wrapped in SC-EVs and mediated the development of CCI-associated memory impairment. Furthermore, α-actinin-4 (ACTN4), ELAV-like protein 4 (ELAVL4) and ubiquitin-specific peptidase 9 X-linked (USP9X) were demonstrated to be important downstream target genes for miR-142-5p-mediated regulation of dendritic spine damage in hippocampal neurons from CCI rats. Conclusion: Together, these findings suggest that SCs-EVs and/or their cargo miR-142-5p may be potential therapeutic targets for memory impairment associated with CNP. [ABSTRACT FROM AUTHOR]
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- 2024
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33. A Four-Week High-Fat Diet Induces Anxiolytic-like Behaviors through Mature BDNF in the mPFC of Mice.
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Huang, Huixian, Huang, Jia, Lu, Wensi, Huang, Yanjun, Luo, Ran, Bathalian, Luqman, Chen, Ming, and Wang, Xuemin
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- *
HIGH-fat diet , *BRAIN-derived neurotrophic factor , *POSTSYNAPTIC density protein , *DENDRITIC spines , *PROTEIN-tyrosine kinases - Abstract
The effect of a high-fat diet (HFD) on mood is a widely debated topic, with the underlying mechanisms being poorly understood. This study explores the anxiolytic effects of a four-week HFD in C57BL/6 mice. Five-week-old mice were exposed to either an HFD (60% calories from fat) or standard chow diet (CD) for four weeks, followed by cannula implantation, virus infusion, behavioral tests, and biochemical assays. Results revealed that four weeks of an HFD induced anxiolytic-like behaviors and increased the protein levels of mature brain-derived neurotrophic factor (mBDNF) and phosphorylated tyrosine kinase receptor B (p-TrkB) in the medial prefrontal cortex (mPFC). Administration of a BDNF-neutralizing antibody to the mPFC reversed HFD-induced anxiolytic-like behaviors. Elevated BDNF levels were observed in both neurons and astrocytes in the mPFC of HFD mice. Additionally, these mice exhibited a higher number of dendritic spines in the mPFC, as well as upregulation of postsynaptic density protein 95 (PSD95). Furthermore, mRNA levels of the N6-methyladenosine (m6A) demethylase, fat mass and obesity-associated protein (FTO), and the hydrolase matrix metalloproteinase-9 (MMP9), also increased in the mPFC. These findings suggest that an HFD may induce FTO and MMP9, which could potentially regulate BDNF processing, contributing to anxiolytic-like behaviors. This study proposes potential molecular mechanisms that may underlie HFD-induced anxiolytic behaviors. [ABSTRACT FROM AUTHOR]
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- 2024
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34. Functional Inhibition of Katanin Affects Synaptic Plasticity.
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Lombino, Franco L., Schwarz, Jürgen R., Pechmann, Yvonne, Schweizer, Michaela, Jark, Rebecca, Stange, Oliver, Glatzel, Markus, Gee, Christine E., Hausrat, Torben J., Gromova, Kira V., and Kneussel, Matthias
- Subjects
- *
NEUROPLASTICITY , *LONG-term potentiation , *POSTSYNAPTIC potential , *GABA receptors , *MICROTUBULES , *CELL division , *EXCITATORY amino acids , *DEVELOPMENTAL neurobiology - Abstract
Dynamic microtubules critically regulate synaptic functions, but the role of microtubule severing in these processes is barely understood. Katanin is a neuronally expressed microtubule-severing complex regulating microtubule number and length in cell division or neurogenesis; however, its potential role in synaptic functions has remained unknown. Studying mice from both sexes, we found that katanin is abundant in neuronal dendrites and can be detected at individual excitatory spine synapses. Overexpression of a dominant-negative ATPase-deficient katanin subunit to functionally inhibit severing alters the growth of microtubules in dendrites, specifically at premature but not mature neuronal stages without affecting spine density. Notably, interference with katanin function prevented structural spine remodeling following single synapse glutamate uncaging and significantly affected the potentiation of AMPA-receptor-mediated excitatory currents after chemical induction of long-term potentiation. Furthermore, katanin inhibition reduced the invasion of microtubules into fully developed spines. Our data demonstrate that katanin-mediated microtubule severing regulates structural and functional plasticity at synaptic sites. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Firing Alterations of Neurons in Alzheimer's Disease: Are They Merely a Consequence of Pathogenesis or a Pivotal Component of Disease Progression?
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Tzavellas, Nikolaos P., Tsamis, Konstantinos I., Katsenos, Andreas P., Davri, Athena S., Simos, Yannis V., Nikas, Ilias P., Bellos, Stefanos, Lekkas, Panagiotis, Kanellos, Foivos S., Konitsiotis, Spyridon, Labrakakis, Charalampos, Vezyraki, Patra, and Peschos, Dimitrios
- Subjects
- *
ALZHEIMER'S disease , *ACTION potentials , *POTASSIUM channels , *SODIUM channels , *DISEASE progression , *TAU proteins , *NEUROPLASTICITY , *SYNAPSES , *NEURAL circuitry - Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, yet its underlying causes remain elusive. The conventional perspective on disease pathogenesis attributes alterations in neuronal excitability to molecular changes resulting in synaptic dysfunction. Early hyperexcitability is succeeded by a progressive cessation of electrical activity in neurons, with amyloid beta (Aβ) oligomers and tau protein hyperphosphorylation identified as the initial events leading to hyperactivity. In addition to these key proteins, voltage-gated sodium and potassium channels play a decisive role in the altered electrical properties of neurons in AD. Impaired synaptic function and reduced neuronal plasticity contribute to a vicious cycle, resulting in a reduction in the number of synapses and synaptic proteins, impacting their transportation inside the neuron. An understanding of these neurophysiological alterations, combined with abnormalities in the morphology of brain cells, emerges as a crucial avenue for new treatment investigations. This review aims to delve into the detailed exploration of electrical neuronal alterations observed in different AD models affecting single neurons and neuronal networks. [ABSTRACT FROM AUTHOR]
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- 2024
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36. Sex differences in motor learning flexibility are accompanied by sex differences in mushroom spine pruning of the mouse primary motor cortex during adolescence
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Michael Tekin, Hui Shen, and Sheryl S. Smith
- Subjects
GABAA receptor ,alpha-4 ,dendritic spine ,motor cortex ,sex differences ,motor learning ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
BackgroundAlthough males excel at motor tasks requiring strength, females exhibit greater motor learning flexibility. Cognitive flexibility is associated with low baseline mushroom spine densities achieved by pruning which can be triggered by α4βδ GABAA receptors (GABARs); defective synaptic pruning impairs this process.MethodsWe investigated sex differences in adolescent pruning of mushroom spine pruning of layer 5 pyramidal cells of primary motor cortex (L5M1), a site essential for motor learning, using microscopic evaluation of Golgi stained sections. We assessed α4GABAR expression using immunohistochemical and electrophysiological techniques (whole cell patch clamp responses to 100 nM gaboxadol, selective for α4βδ GABARs). We then compared performance of groups with different post-pubertal mushroom spine densities on motor learning (constant speed) and learning flexibility (accelerating speed following constant speed) rotarod tasks.ResultsMushroom spines in proximal L5M1 of female mice decreased >60% from PND35 (puberty onset) to PND56 (Pubertal: 2.23 ± 0.21 spines/10 μm; post-pubertal: 0.81 ± 0.14 spines/10 μm, P < 0.001); male mushroom spine density was unchanged. This was due to greater α4βδ GABAR expression in the female (P < 0.0001) because α4 -/- mice did not exhibit mushroom spine pruning. Although motor learning was similar for all groups, only female wild-type mice (low mushroom spine density) learned the accelerating rotarod task after the constant speed task (P = 0.006), a measure of motor learning flexibility.ConclusionsThese results suggest that optimal motor learning flexibility of female mice is associated with low baseline levels of post-pubertal mushroom spine density in L5M1 compared to male and female α4 -/- mice.
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- 2024
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37. Effects of esketamine on depression-like behavior and dendritic spine plasticity in the prefrontal cortex neurons of spared nerve injury-induced depressed mice
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Bixin Huang, Xiaoling Li, Yuling Zheng, Ying Mai, and Zhongqi Zhang
- Subjects
Esketamine ,Depression ,CRMP2 ,Spared nerve injury ,Dendritic spine ,Prefrontal cortex ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression.
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- 2024
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38. Super-resolution imaging reveals the relationship between CaMKIIβ and drebrin within dendritic spines
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Hiroyuki Yamazaki, Noriko Koganezawa, Hideaki Yokoo, Yuko Sekino, and Tomoaki Shirao
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Drebrin ,CaMKII ,Actin cytoskeleton ,Dendritic spine ,Plasticity ,Super-resolution microscopy ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Dendritic spines are unique postsynaptic structures that emerge from the dendrites of neurons. They undergo activity-dependent morphological changes known as structural plasticity. The changes involve actin cytoskeletal remodeling, which is regulated by actin-binding proteins. CaMKII is a crucial molecule in synaptic plasticity. Notably, CaMKIIβ subtype is known to bind to filamentous-actin and is closely involved in structural plasticity. We have shown that CaMKIIβ binds to drebrin, and is localized in spines as both drebrin-dependent and drebrin-independent pools. However, the nanoscale relationship between drebrin and CaMKIIβ within dendritic spines has not been clarified. In this study, we used stochastic optical reconstruction microscopy (STORM) to examine the detailed localization of these proteins. STORM imaging showed that CaMKIIβ co-localized with drebrin in the core region of spines, and localized in the submembrane region of spines without drebrin. Interestingly, the dissociation of CaMKIIβ and drebrin in the core region was induced by NMDA receptor activation. In drebrin knockdown neurons, CaMKIIβ was decreased in the core region but not in the submembrane region. Together it indicates that the clustering of CaMKIIβ in the spine core region is dependent on drebrin. These findings suggest that drebrin-dependent CaMKIIβ is in a standby state before its activation.
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- 2024
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39. Low-intensity transcranial ultrasound stimulation improves memory in vascular dementia by enhancing neuronal activity and promoting spine formation
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Jiamin Pei, Cong Zhang, Xiao Zhang, Zhe Zhao, Xiangjian Zhang, and Yi Yuan
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Transcranial ultrasound stimulation ,VD ,Memory ability ,Neuron activity ,Dendritic spine ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Memory is closely associated with neuronal activity and dendritic spine formation. Low-intensity transcranial ultrasound stimulation (TUS) improves the memory of individuals with vascular dementia (VD). However, it is unclear whether neuronal activity and dendritic spine formation under ultrasound stimulation are involved in memory improvement in VD. In this study, we found that seven days of TUS improved memory in VD model while simultaneously increasing pyramidal neuron activity, promoting dendritic spine formation, and reducing dendritic spine elimination. These effects lasted for 7 days but disappeared on 14 d after TUS. Neuronal activity and dendritic spine formation strongly corresponded to improvements in memory behavior over time. In addition, we also found that the memory, neuronal activity and dendritic spine of VD mice cannot be restored again by TUS of 7 days after 28 d. Collectively, these findings suggest that TUS increases neuronal activity and promotes dendritic spine formation and is thus important for improving memory in patients with VD.
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- 2024
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40. Aegle marmelos (L.) Leaf Extract Improves Symptoms of Memory Loss Induced by Scopolamine in Rats.
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Thongsopha, Chanida, Chaiwut, Thanasit, Thaweekhotr, Pornnarez, Sudwan, Paiwan, Phasukdee, Noppadol, and Quiggins, Ranida
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TROPANES ,BAEL (Tree) ,ALKALOIDS ,MEMORY loss ,SCOPOLAMINE ,DENDRITIC spines ,ALZHEIMER'S disease ,HEMATOXYLIN & eosin staining - Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease that results in memory impairment. Aegle marmelos (L.) Correa (AM) is used as a traditional medicine. AM leaves have the potential to inhibit acetylcholinesterase activity. This study used scopolamine to induce AD in rats. The aim of this study was to investigate the effects of AM leaf extract using this model. Motor and memory functions were tested by the motor activity and Morris water maze (MWM) tests, respectively. The density of the synaptophysin and dendritic spines in the CA1 were detected by immunofluorescence and Golgi impregnation, respectively. The hippocampal histology was reviewed by H&E staining. After the treatment, the latency times in the MWM tests of the AD groups reduced, while the motor activities showed no difference. The density of the synaptophysin of the AD groups increased after the treatments, and that of the dendritic spines also increased in all AD groups post-treatment. The hippocampal tissue also recovered. AM leaf extract can improve cognitive impairment in AD models by maintaining the presynaptic vesicle proteins and dendritic spines in a dose-dependent manner. [ABSTRACT FROM AUTHOR]
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- 2024
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41. Knockout of the intellectual disability-linked gene Hs6st2 in mice decreases heparan sulfate 6-O-sulfation, impairs dendritic spines of hippocampal neurons, and affects memory.
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Moon, Sohyun, Lee, Hiu Ham, Archer-Hartmann, Stephanie, Nagai, Naoko, Mubasher, Zainab, Parappurath, Mahima, Ahmed, Laiba, Ramos, Raddy L, Kimata, Koji, Azadi, Parastoo, Cai, Weikang, and Zhao, Jerry Yingtao
- Subjects
- *
HEPARAN sulfate , *DENDRITIC spines , *PYRAMIDAL neurons , *NEURONS , *CEREBRAL cortex , *HIPPOCAMPUS (Brain) - Abstract
Heparan sulfate (HS) is a linear polysaccharide that plays a key role in cellular signaling networks. HS functions are regulated by its 6-O-sulfation, which is catalyzed by three HS 6-O-sulfotransferases (HS6STs). Notably, HS6ST2 is mainly expressed in the brain and HS6ST2 mutations are linked to brain disorders, but the underlying mechanisms remain poorly understood. To determine the role of Hs6st2 in the brain, we carried out a series of molecular and behavioral assessments on Hs6st2 knockout mice. We first carried out strong anion exchange-high performance liquid chromatography and found that knockout of Hs6st2 moderately decreases HS 6-O-sulfation levels in the brain. We then assessed body weights and found that Hs6st2 knockout mice exhibit increased body weight, which is associated with abnormal metabolic pathways. We also performed behavioral tests and found that Hs6st2 knockout mice showed memory deficits, which recapitulate patient clinical symptoms. To determine the molecular mechanisms underlying the memory deficits, we used RNA sequencing to examine transcriptomes in two memory-related brain regions, the hippocampus and cerebral cortex. We found that knockout of Hs6st2 impairs transcriptome in the hippocampus, but only mildly in the cerebral cortex. Furthermore, the transcriptome changes in the hippocampus are enriched in dendrite and synapse pathways. We also found that knockout of Hs6st2 decreases HS levels and impairs dendritic spines in hippocampal CA1 pyramidal neurons. Taken together, our study provides novel molecular and behavioral insights into the role of Hs6st2 in the brain, which facilitates a better understanding of HS6ST2 and HS-linked brain disorders. [ABSTRACT FROM AUTHOR]
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- 2024
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42. Cell-autonomous reduction of CYFIP2 changes dendrite length, dendritic protrusion morphology, and inhibitory synapse density in the hippocampal CA1 pyramidal neurons of 17-month-old mice.
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Kim, Yoonhee, Ma, Ruiying, Zhang, Yinhua, Kang, Hyae Rim, Kim, U Suk, and Han, Kihoon
- Subjects
PYRAMIDAL neurons ,ALZHEIMER'S disease ,DENDRITES ,GENETIC translation ,DENDRITIC spines ,NEURONS - Abstract
The cytoplasmic FMR1-interacting protein 2 (CYFIP2) have diverse molecular functions in neurons, including the regulation of actin polymerization, mRNA translation, and mitochondrial morphology and function. Mutations in the CYFIP2 gene are associated with early-onset epilepsy and neurodevelopmental disorders, while decreases in its protein levels are linked to Alzheimer's disease (AD). Notably, previous research has revealed AD-like phenotypes, such as dendritic spine loss, in the hippocampal CA1 pyramidal neurons of 12-month-old Cyfip2 heterozygous mice but not of age-matched CA1 pyramidal neuron-specific Cyfip2 conditional knock-out (cKO) mice. This study aims to investigate whether dendritic spine loss in Cyfip2 cKO mice is merely delayed compared to Cyfip2 heterozygous mice, and to explore further neuronal phenotypes regulated by CYFIP2 in aged mice. We characterized dendrite and dendritic protrusion morphologies, along with excitatory/inhibitory synapse densities in CA1 pyramidal neurons of 17-month-old Cyfip2 cKO mice. Overall dendritic branching was normal, with a reduction in the length of basal, not apical, dendrites in CA1 pyramidal neurons of Cyfip2 cKO mice. Furthermore, while dendritic protrusion density remained normal, alterations were observed in the length of mushroom spines and the head volume of stubby spines in basal, not apical, dendrites of Cyfip2 cKO mice. Although excitatory synapse density remained unchanged, inhibitory synapse density increased in apical, not basal, dendrites of Cyfip2 cKO mice. Consequently, a cell-autonomous reduction of CYFIP2 appears insufficient to induce dendritic spine loss in CA1 pyramidal neurons of aged mice. However, CYFIP2 is required to maintain normal dendritic length, dendritic protrusion morphology, and inhibitory synapse density. [ABSTRACT FROM AUTHOR]
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- 2024
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43. Cadherin-13 Maintains Retinotectal Synapses via Transneuronal Interactions.
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Matcham, Angela C., Toma, Kenichi, Tsai, Nicole Y., Sze, Christina J., Pin-Yeh Lin, Stewart, Ilaria F., and Xin Duan
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- *
SUPERIOR colliculus , *DENDRITIC spines , *RETINAL ganglion cells , *SYNAPSES , *CENTRAL nervous system , *CELLULAR recognition - Abstract
Maintaining precise synaptic contacts between neuronal partners is critical to ensure the proper functioning of the mammalian central nervous system (CNS). Diverse cell recognition molecules, such as classic cadherins (Cdhs), are part of the molecular machinery mediating synaptic choices during development and synaptic maintenance. Yet, the principles governing neuron-neuron wiring across diverse CNS neuron types remain largely unknown. The retinotectal synapses, connections from the retinal ganglion cells (RGCs) to the superior collicular (SC) neurons, offer an ideal experimental system to reveal molecular logic underlying synaptic choices and formation. This is due to the retina's unidirectional and laminar-restricted projections to the SC and the large databases of presynaptic RGC subtypes and postsynaptic SC neuronal types. Here, we focused on determining the role of Type II Cdhs in wiring the retinotectal synapses. We surveyed Cdhs expression patterns at neuronal resolution and revealed that Cdh13 is enriched in the wide-field neurons in the superficial SC (sSC). In either the Cdh13 null mutant or selective adult deletion within the wide-field neurons, there is a significant reduction of spine densities in the distal dendrites of these neurons in both sexes. Additionally, Cdh13 removal from presynaptic RGCs reduced dendritic spines in the postsynaptic wide-field neurons. Cdh13-expressing RGCs use differential mechanisms than aRGCs and On-Off Direction-Selective Ganglion Cells (ooDSGCs) to form specific retinotectal synapses. The results revealed a selective transneuronal interaction mediated by Cdh13 to maintain proper retinotectal synapses in vivo. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Activity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIa Function.
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Claiborne, Nicole, Anisimova, Margarita, and Zito, Karen
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DENDRITIC spines , *GLUTAMATE receptors , *LONG-term potentiation , *SPINE , *GLUTAMIC acid - Abstract
The outgrowth and stabilization of nascent dendritic spines are crucial processes underlying learning and memory. Most new spines retract shortly after growth; only a small subset is stabilized and integrated into the new circuit connections that support learning. New spine stabilization has been shown to rely upon activity-dependent molecular mechanisms that also contribute to long-term potentiation (LTP) of synaptic strength. Indeed, disruption of the activity-dependent targeting of the kinase CaMKIIα to the GluN2B subunit of the NMDA-type glutamate receptor disrupts both LTP and activity-dependent stabilization of new spines. Yet it is not known which of CaMKIIα's many enzymatic and structural functions are important for new spine stabilization. Here, we used two-photon imaging and photolysis of caged glutamate to monitor the activity-dependent stabilization of new dendritic spines on hippocampal CA1 neurons from mice of both sexes in conditions where CaMKIIα functional and structural interactions were altered. Surprisingly, we found that inhibiting CaMKIIα kinase activity either genetically or pharmacologically did not impair activity-dependent new spine stabilization. In contrast, shRNA knockdown of CaMKIIα abolished activity-dependent new spine stabilization, which was rescued by co-expressing shRNA-resistant full-length CaMKIIα, but not by a truncated monomeric CaMKIIα. Notably, overexpression of phospho-mimetic CaMKIIα-T286D, which exhibits activity-independent targeting to GluN2B, enhanced basal new spine survivorship in the absence of additional glutamatergic stimulation, even when kinase activity was disrupted. Together, our results support a model in which nascent dendritic spine stabilization requires structural and scaffolding interactions mediated by dodecameric CaMKIIα that are independent of its enzymatic activities. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Control of hippocampal synaptic plasticity by microglia–dendrite interactions depends on genetic context in mouse models of Alzheimer's disease.
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Heuer, Sarah E., Keezer, Kelly J., Hewes, Amanda A., Onos, Kristen D., Graham, Kourtney C., Howell, Gareth R., and Bloss, Erik B.
- Abstract
INTRODUCTION: Human data suggest susceptibility and resilience to features of Alzheimer's disease (AD) such as microglia activation and synaptic dysfunction are under genetic control. However, causal relationships between these processes, and how genomic diversity modulates them remain systemically underexplored in mouse models. METHODS: AD‐vulnerable hippocampal neurons were virally labeled in inbred (C57BL/6J) and wild‐derived (PWK/PhJ) APP/PS1 and wild‐type mice, and brain microglia depleted from 4 to 8 months of age. Dendrites were assessed for synapse plasticity changes by evaluating spine densities and morphologies. RESULTS: In C57BL/6J, microglia depletion blocked amyloid‐induced synaptic density and morphology changes. At a finer scale, synaptic morphology on individual branches was dependent on microglia–dendrite physical interactions. Conversely, synapses from PWK/PhJ mice showed remarkable stability in response to amyloid, and no evidence of microglia contact‐dependent changes on dendrites. DISCUSSION: These results demonstrate that microglia‐dependent synaptic alterations in specific AD‐vulnerable projection pathways are differentially controlled by genetic context. [ABSTRACT FROM AUTHOR]
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- 2024
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46. Calcineurin inhibition protects against dopamine toxicity and attenuates behavioral decline in a Parkinson’s disease model
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Rupsha Mondal, Chayan Banerjee, Sumangal Nandy, Moumita Roy, and Joy Chakraborty
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Dopamine toxicity ,Mitochondrial fragmentation ,Calcineurin ,Parkinson’s disease ,L-DOPA therapy ,Dendritic spine ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Parkinson’s disease (PD), a highly prevalent neuro-motor disorder is caused due to progressive loss of dopaminergic (DAergic) neurons at substantia nigra region of brain. This leads to depleted dopamine (DA) content at striatum, thus affecting the fine tuning of basal ganglia. In patients, this imbalance is manifested by akinesia, catalepsy and tremor. PD associated behavioral dysfunctions are frequently mitigated by l-DOPA (LD) therapy, a precursor for DA synthesis. Due to progressive neurodegeneration, LD eventually loses applicability in PD. Although DA is cytotoxic, it is unclear whether LD therapy can accelerate PD progression or not. LD itself does not lead to neurodegeneration in vivo, but previous reports demonstrate that LD treatment mediated excess DA can potentiate neurotoxicity when PD associated genetic or epigenetic aberrations are involved. So, minimizing DA toxicity during the therapy is an absolute necessity to halt or slowdown PD progression. The two major contributing factors associated with DA toxicity are: degradation by Monoamine oxidase and DAquinone (DAQ) formation. Results Here, we report that apoptotic mitochondrial fragmentation via Calcineurin (CaN)-DRP1 axis is a common downstream event for both these initial cues, inhibiting which can protect cells from DA toxicity comprehensively. No protective effect is observed, in terms of cell survival when only PxIxIT domain of CaN is obstructed, demonstrating the importance to block DRP1-CaN axis specifically. Further, evaluation of the impact of DA exposure on PD progression in a mice model reveal that LD mediated behavioral recovery diminishes with time, mostly because of continued DAergic cell death and dendritic spine loss at striatum. CaN inhibition, alone or in combination with LD, offer long term behavioral protection. This protective effect is mediated specifically by hindering CaN-DRP1 axis, whereas inhibiting interaction between CaN and other substrates, including proteins involved in neuro-inflammation, remained ineffective when LD is co-administered. Conclusions In this study, we conclude that DA toxicity can be circumvented by CaN inhibition and it can mitigate PD related behavioral aberrations by protecting neuronal architecture at striatum. We propose that CaN inhibitors might extend the therapeutic efficacy of LD treatment.
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- 2023
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47. DiGeorge syndrome critical region gene 2 (DGCR2), a schizophrenia risk gene, regulates dendritic spine development through cell adhesion
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Dongyan Ren, Bin Luo, Peng Chen, Lulu Yu, Mingtao Xiong, Zhiqiang Fu, Tian Zhou, Wen-Bing Chen, and Erkang Fei
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DiGeorge syndrome critical region gene 2 (DGCR2) ,22q11.2 deletion syndrome (22q11DS) ,Anxiety ,Cell adhesion ,Dendritic spine ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract Background Dendritic spines are the sites of excitatory synapses on pyramidal neurons, and their development is crucial for neural circuits and brain functions. The spine shape, size, or number alterations are associated with neurological disorders, including schizophrenia. DiGeorge syndrome critical region gene 2 (DGCR2) is one of the deleted genes within the 22q11.2 deletion syndrome (22q11DS), which is a high risk for developing schizophrenia. DGCR2 expression was reduced in schizophrenics. However, the pathophysiological mechanism of DGCR2 in schizophrenia or 22q11DS is still unclear. Results Here, we report that DGCR2 expression was increased during the neurodevelopmental period and enriched in the postsynaptic densities (PSDs). DGCR2-deficient hippocampal neurons formed fewer spines. In agreement, glutamatergic transmission and synaptic plasticity were decreased in the hippocampus of DGCR2-deficient mice. Further molecular studies showed that the extracellular domain (ECD) of DGCR2 is responsible for its transcellular interaction with cell adhesion molecule Neurexin1 (NRXN1) and spine development. Consequently, abnormal behaviors, like anxiety, were observed in DGCR2-deficient mice. Conclusions These observations indicate that DGCR2 is a novel cell adhesion molecule required for spine development and synaptic plasticity, and its deficiency induces abnormal behaviors in mice. This study provides a potential pathophysiological mechanism of DGCR2 in 22q11DS and related mental disorders.
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- 2023
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48. PAK3 downregulation induces cognitive impairment following cranial irradiation
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Haksoo Lee, Hyunkoo Kang, Changjong Moon, and BuHyun Youn
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cranial radiation ,cognitive impairment ,dendritic spine ,intranasal administration ,microRNA ,p21-activated kinase 3 ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Cranial irradiation is used for prophylactic brain radiotherapy as well as the treatment of primary brain tumors. Despite its high efficiency, it often induces unexpected side effects, including cognitive dysfunction. Herein, we observed that mice exposed to cranial irradiation exhibited cognitive dysfunction, including altered spontaneous behavior, decreased spatial memory, and reduced novel object recognition. Analysis of the actin cytoskeleton revealed that ionizing radiation (IR) disrupted the filamentous/globular actin (F/G-actin) ratio and downregulated the actin turnover signaling pathway p21-activated kinase 3 (PAK3)-LIM kinase 1 (LIMK1)-cofilin. Furthermore, we found that IR could upregulate microRNA-206–3 p (miR-206–3 p) targeting PAK3. As the inhibition of miR-206–3 p through antagonist (antagomiR), IR-induced disruption of PAK3 signaling is restored. In addition, intranasal administration of antagomiR-206–3 p recovered IR-induced cognitive impairment in mice. Our results suggest that cranial irradiation-induced cognitive impairment could be ameliorated by regulating PAK3 through antagomiR-206–3 p, thereby affording a promising strategy for protecting cognitive function during cranial irradiation, and promoting quality of life in patients with radiation therapy.
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- 2023
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49. Cortical circuit dynamics underlying motor skill learning: from rodents to humans.
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Emily Kogan, Ju Lu, and Yi Zuo
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MOTOR learning ,MOTOR ability ,NEURAL circuitry ,RODENTS ,MOTOR cortex ,PREMOTOR cortex - Abstract
Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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50. Hyaluronic Acid Conjugated with 17β-Estradiol Effectively Alleviates Estropause-Induced Cognitive Deficits in Rats.
- Author
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Chen, Mu-Hsuan, Lin, Hsiao-Chun, Chao, Tzu, Lee, Viola Szu-Yuan, Hou, Chia-Lung, Wang, Tsyr-Jiuan, and Chen, Jeng-Rung
- Subjects
- *
PYRAMIDAL neurons , *HIPPOCAMPUS (Brain) , *SEPTUM (Brain) , *HYALURONIC acid , *DENDRITIC spines , *ALZHEIMER'S disease , *ESTRUS - Abstract
Women are at a higher risk of cognitive impairments and Alzheimer's disease (AD), particularly after the menopause, when the estrous cycle becomes irregular and diminishes. Numerous studies have shown that estrogen deficiency, especially estradiol (E2) deficiency, plays a key role in this phenomenon. Recently, a novel polymeric drug, hyaluronic acid–17β-estradiol conjugate (HA-E2), has been introduced for the delivery of E2 to brain tissues. Studies have indicated that HA-E2 crosses the blood–brain barrier (BBB) and facilitates a prolonged E2 release profile while lowering the risk of estrogen-supplement-related side effects. In this study, we used ovariohysterectomy (OHE) rats, a postmenopausal cognitive deficit model, to explore the effect of a 2-week HA-E2 treatment (210 ng/kg body weight, twice a week) on the cholinergic septo-hippocampal innervation system, synaptic transmission in hippocampal pyramidal neurons and cognitive improvements. Our study revealed an 11% rise in choline acetyltransferase (ChAT) expression in both the medial septal nucleus (MS nucleus) and the hippocampus, along with a 14–18% increase in dendritic spine density in hippocampal pyramidal neurons, following HA-E2 treatment in OHE rats. These enhancements prompted the recovery of cognitive functions such as spatial learning and memory. These findings suggest that HA-E2 may prevent and improve estrogen-deficiency-induced cognitive impairment and AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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