Frontiers in Synaptic Neuroscience最新文献

{"title":"The plasticity of cardiac sympathetic nerves and its clinical implication in cardiovascular disease.","authors":"Hideaki Kanazawa,&nbsp;Keiichi Fukuda","doi":"10.3389/fnsyn.2022.960606","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.960606","url":null,"abstract":"<p><p>The heart is electrically and mechanically controlled by the autonomic nervous system, which consists of both the sympathetic and parasympathetic systems. It has been considered that the sympathetic and parasympathetic nerves regulate the cardiomyocytes' performance independently; however, recent molecular biology approaches have provided a new concept to our understanding of the mechanisms controlling the diseased heart through the plasticity of the autonomic nervous system. Studies have found that cardiac sympathetic nerve fibers in hypertrophic ventricles strongly express an immature neuron marker and simultaneously cause deterioration of neuronal cellular function. This phenomenon was explained by the rejuvenation of cardiac sympathetic nerves. Moreover, heart failure and myocardial infarction have been shown to cause cholinergic trans-differentiation of cardiac sympathetic nerve fibers <i>via</i> gp130-signaling cytokines secreted from the failing myocardium, affecting cardiac performance and prognosis. This phenomenon is thought to be one of the adaptations that prevent the progression of heart disease. Recently, the concept of using device-based neuromodulation therapies to attenuate sympathetic activity and increase parasympathetic (vagal) activity to treat cardiovascular disease, including heart failure, was developed. Although several promising preclinical and pilot clinical studies using these strategies have been conducted, the results of clinical efficacy vary. In this review, we summarize the current literature on the plasticity of cardiac sympathetic nerves and propose potential new therapeutic targets for heart disease.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33485457","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Killer or helper? The mechanism underlying the role of adenylate activated kinase in sound conditioning.","authors":"Rui Zhao,&nbsp;Changhong Ma,&nbsp;Minjun Wang,&nbsp;Xinxin Li,&nbsp;Wei Liu,&nbsp;Lin Shi,&nbsp;Ning Yu","doi":"10.3389/fnsyn.2022.940788","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.940788","url":null,"abstract":"<p><strong>Objective: </strong>To investigate whether sound conditioning influences auditory system protection by activating adenylate activated kinase (AMPK), and if such adaption protects ribbon synapses from high-intensity noise exposure.</p><p><strong>Materials and methods: </strong>CBA mice (12 weeks old) were randomly divided into four groups (<i>n</i> = 24 mice per group): control, sound conditioning (SC), sound conditioning plus noise exposure (SC+NE), and noise exposure (NE). Hearing thresholds were assessed before testing, after sound conditioning, and 0, 3, 7, and 14 days after 110 dB noise exposure. Amplitudes and latencies of wave I at 90 dB intensity were assessed before test, after conditioning, and at 0 and 14 days after 110 dB noise exposure. One cochlea from each mouse was subjected to immunofluorescence staining to assess synapse numbers and AMPK activation, while the other cochlea was analyzed for phosphorylated adenylate activated kinase (p-AMPK) protein expression by western blot.</p><p><strong>Results: </strong>There was no significant difference in auditory brainstem response (ABR) threshold between SC and control mice. The degree of hearing loss of animals in the two SC groups was significantly reduced compared to the NE group after 110 dB noise exposure. Animals in the SC group showed faster recovery to normal thresholds, and 65 dB SPL sound conditioning had a stronger auditory protection effect. After sound conditioning, the amplitude of ABR I wave in the SC group was higher than that in the control group. Immediately after noise exposure (D0), the amplitudes of ABR I wave decreased significantly in all groups; the most significant decrease was in the NE group, with amplitude in 65SC+NE group significantly higher than that in the 85SC+NE group. Wave I latency in the SC group was significantly shorter than that in the control group. At D0, latency was prolonged in the NE group compared with the control group. In contrast, there was no significant difference in latency between the 65SC+NE and 85SC+NE groups. Further, at D14, there was no significant difference between the NE and control groups, while latency remained significantly shorter in the 65SC+NE and 85SC+NE groups compared with controls. Number of ribbon synapses in SC mice did not differ significantly from that in controls. After 110 dB noise exposure, there were significantly more ribbon synapses in the SC+NE group than the NE group. Ribbon synapses of all groups were recovered 14 days after the noise exposure, while the SC group had a shorter recovery time than the non-SC groups (<i>p</i> < 0.05). AMPK was highly activated in the SC group, and p-AMPK expression was detected; however, after 110 dB noise exposure, the strongest protein expression was detected in the NE group, followed by the SC+NE groups, and the lowest protein expression was detected in the control group.</p><p><strong>Conclusion: </strong>Sound conditioning animals were more noise resistant and","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9490174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33485458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editorial: Quantifying and controlling the nano-architecture of neuronal synapses.","authors":"Xiaobing Chen,&nbsp;Thomas Kuner,&nbsp;Thomas A Blanpied","doi":"10.3389/fnsyn.2022.1024073","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.1024073","url":null,"abstract":"COPYRIGHT © 2022 Chen, Kuner and Blanpied. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Quantifying and controlling the nano-architecture of neuronal synapses","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9491271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33485456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism.","authors":"Montserrat Padilla-Orozco,&nbsp;Mariana Duhne,&nbsp;Alejandra Fuentes-Serrano,&nbsp;Aidán Ortega,&nbsp;Elvira Galarraga,&nbsp;José Bargas,&nbsp;Esther Lara-González","doi":"10.3389/fnsyn.2022.945816","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.945816","url":null,"abstract":"<p><p>Parkinson's disease is a neurodegenerative ailment generated by the loss of dopamine in the basal ganglia, mainly in the striatum. The disease courses with increased striatal levels of acetylcholine, disrupting the balance among these modulatory transmitters. These modifications disturb the excitatory and inhibitory balance in the striatal circuitry, as reflected in the activity of projection striatal neurons. In addition, changes in the firing pattern of striatal tonically active interneurons during the disease, including cholinergic interneurons (CINs), are being searched. Dopamine-depleted striatal circuits exhibit pathological hyperactivity as compared to controls. One aim of this study was to show how striatal CINs contribute to this hyperactivity. A second aim was to show the contribution of extrinsic synaptic inputs to striatal CINs hyperactivity. Electrophysiological and calcium imaging recordings in Cre-mice allowed us to evaluate the activity of dozens of identified CINs with single-cell resolution in <i>ex vivo</i> brain slices. CINs show hyperactivity with bursts and silences in the dopamine-depleted striatum. We confirmed that the intrinsic differences between the activity of control and dopamine-depleted CINs are one source of their hyperactivity. We also show that a great part of this hyperactivity and firing pattern change is a product of extrinsic synaptic inputs, targeting CINs. Both glutamatergic and GABAergic inputs are essential to sustain hyperactivity. In addition, cholinergic transmission through nicotinic receptors also participates, suggesting that the joint activity of CINs drives the phenomenon; since striatal CINs express nicotinic receptors, not expressed in striatal projection neurons. Therefore, CINs hyperactivity is the result of changes in intrinsic properties and excitatory and inhibitory inputs, in addition to the modification of local circuitry due to cholinergic nicotinic transmission. We conclude that CINs are the main drivers of the pathological hyperactivity present in the striatum that is depleted of dopamine, and this is, in part, a result of extrinsic synaptic inputs. These results show that CINs may be a main therapeutic target to treat Parkinson's disease by intervening in their synaptic inputs.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9485566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33478819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting prefrontal cortex GABAergic microcircuits for the treatment of alcohol use disorder.","authors":"Kenneth N Fish, Max E Joffe","doi":"10.3389/fnsyn.2022.936911","DOIUrl":"10.3389/fnsyn.2022.936911","url":null,"abstract":"<p><p>Developing novel treatments for alcohol use disorders (AUDs) is of paramount importance for improving patient outcomes and alleviating the suffering related to the disease. A better understanding of the molecular and neurocircuit mechanisms through which alcohol alters brain function will be instrumental in the rational development of new efficacious treatments. Clinical studies have consistently associated the prefrontal cortex (PFC) function with symptoms of AUDs. Population-level analyses have linked the PFC structure and function with heavy drinking and/or AUD diagnosis. Thus, targeting specific PFC cell types and neural circuits holds promise for the development of new treatments. Here, we overview the tremendous diversity in the form and function of inhibitory neuron subtypes within PFC and describe their therapeutic potential. We then summarize AUD population genetics studies, clinical neurophysiology findings, and translational neuroscience discoveries. This study collectively suggests that changes in fast transmission through PFC inhibitory microcircuits are a central component of the neurobiological effects of ethanol and the core symptoms of AUDs. Finally, we submit that there is a significant and timely need to examine sex as a biological variable and human postmortem brain tissue to maximize the efforts in translating findings to new clinical treatments.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9465392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40358807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular basis of learning and memory in the carotid body.","authors":"Olivia M S Gold,&nbsp;Emma N Bardsley,&nbsp;Anna P Ponnampalam,&nbsp;Audrys G Pauza,&nbsp;Julian F R Paton","doi":"10.3389/fnsyn.2022.902319","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.902319","url":null,"abstract":"<p><p>The carotid body is the primary peripheral chemoreceptor in the body, and critical for respiration and cardiovascular adjustments during hypoxia. Yet considerable evidence now implicates the carotid body as a multimodal sensor, mediating the chemoreflexes of a wide range of physiological responses, including pH, temperature, and acidosis as well as hormonal, glucose and immune regulation. How does the carotid body detect and initiate appropriate physiological responses for these diverse stimuli? The answer to this may lie in the structure of the carotid body itself. We suggest that at an organ-level the carotid body is comparable to a miniature brain with compartmentalized discrete regions of clustered glomus cells defined by their neurotransmitter expression and receptor profiles, and with connectivity to defined reflex arcs that play a key role in initiating distinct physiological responses, similar in many ways to a switchboard that connects specific inputs to selective outputs. Similarly, within the central nervous system, specific physiological outcomes are co-ordinated, through signaling via distinct neuronal connectivity. As with the brain, we propose that highly organized cellular connectivity is critical for mediating co-ordinated outputs from the carotid body to a given stimulus. Moreover, it appears that the rudimentary components for synaptic plasticity, and learning and memory are conserved in the carotid body including the presence of glutamate and GABAergic systems, where evidence pinpoints that pathophysiology of common diseases of the carotid body may be linked to deviations in these processes. Several decades of research have contributed to our understanding of the central nervous system in health and disease, and we discuss that understanding the key processes involved in neuronal dysfunction and synaptic activity may be translated to the carotid body, offering new insights and avenues for therapeutic innovation.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40335404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vagally-mediated heart block after myocardial infarction associated with plasticity of epicardial neurons controlling the atrioventricular node.","authors":"John D Tompkins,&nbsp;Una Buckley,&nbsp;Siamak Salavatian,&nbsp;Kalyanam Shivkumar,&nbsp;Jeffrey L Ardell","doi":"10.3389/fnsyn.2022.960458","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.960458","url":null,"abstract":"<p><p>Imbalances in the opposing actions of sympathetic and parasympathetic nerves controlling the heart enhance risk for arrhythmia and sudden cardiac death after myocardial infarction (MI). Plasticity in peripheral neuron function may underlie the observed changes in cardiomotor nerve activity. We studied vagal control of the heart in pigs after chronic infarction of the left ventricle. Stimulation of the cervical vagus nerve produced greater bradycardic responses 8-weeks after MI. Recordings of epicardial electrocardiograms demonstrate increased severity and duration of atrioventricular (AV) block in MI-pigs during 20 Hz vagal stimulation. Intracellular voltage recordings from isolated neurons of the inferior vena cava-inferior left atrium (IVC-ILA) ganglionated plexus, a cluster of epicardial neurons receiving innervation from the vagus known to regulate the AV node, were used to assess plasticity of membrane and synaptic physiology of intrinsic cardiac neurons (ICNs) after MI. Changes to both passive and active membrane properties were observed, including more negative resting membrane potentials and greater input resistances in MI-pig ICNs, concomitant with a depression of neuronal excitability. Immunoreactivity to pituitary adenylate cyclase-activating polypeptide (PACAP), a cardiotropic peptide known to modulate cardiac neuron excitability, was localized to perineuronal varicosities surrounding pig IVC-ILA neurons. Exogenous application of PACAP increased excitability of control but not MI-ICNs. Stimulation (20 Hz) of interganglionic nerves in the <i>ex vivo</i> whole-mount preparations elicited slow excitatory postsynaptic potentials (sEPSPs) which persisted in hexamethonium (500 μM), but were blocked by atropine (1 μM), indicating muscarinic receptor-mediated inhibition of M-current. Extracellular application of 1 mM BaCl₂ to inhibit M-current increased neuronal excitability. The muscarine-sensitive sEPSPs were observed more frequently and were of larger amplitude in IVC-ILA neurons from MI animals. In conclusion, we suggest the increased probability of muscarinic sEPSPs play a role in the potentiation of the vagus nerve mediated-slowing of AV nodal conduction following chronic MI. We identify both a novel role of a muscarinic sensitive current in the regulation of synaptic strength at ICNs projecting to the AV node, and demonstrate changes to both intrinsic plasticity and synaptic plasticity of IVC-ILA neurons which may contribute to greater risk for heart block and sudden cardiac death after MI.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9488518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33478816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synaptic spinules are reliable indicators of excitatory presynaptic bouton size and strength and are ubiquitous components of excitatory synapses in CA1 hippocampus.","authors":"Ashley Gore,&nbsp;Amaliya Yurina,&nbsp;Anastasia Yukevich-Mussomeli,&nbsp;Marc Nahmani","doi":"10.3389/fnsyn.2022.968404","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.968404","url":null,"abstract":"<p><p>Synaptic spinules are thin, finger-like projections from one neuron that become embedded within the presynaptic or postsynaptic compartments of another neuron. While spinules are conserved features of synapses across the animal kingdom, their specific function(s) remain unknown. Recent focused ion beam scanning electron microscopy (FIB-SEM) image volume analyses have demonstrated that spinules are embedded within ∼25% of excitatory boutons in primary visual cortex, yet the diversity of spinule sizes, origins, and ultrastructural relationships to their boutons remained unclear. To begin to uncover the function of synaptic spinules, we sought to determine the abundance, origins, and 3D ultrastructure of spinules within excitatory presynaptic spinule-bearing boutons (SBBs) in mammalian CA1 hippocampus and compare them with presynaptic boutons bereft of spinules (non-SBBs). Accordingly, we performed a comprehensive 3D analysis of every excitatory presynaptic bouton, their embedded spinules, and postsynaptic densities, within a 5 nm isotropic FIB-SEM image volume from CA1 hippocampus of an adult male rat. Surprisingly, we found that ∼74% of excitatory presynaptic boutons in this volume contained at least one spinule, suggesting they are fundamental components of excitatory synapses in CA1. In addition, we found that SBBs are 2.5-times larger and have 60% larger postsynaptic densities (PSDs) than non-SBBs. Moreover, synaptic spinules within SBBs are clearly differentiated into two groups: small clathrin-coated spinules, and 29-times larger spinules without clathrin. Together, these findings suggest that the presence of a spinule is a marker for stronger and more stable presynaptic boutons in CA1, and that synaptic spinules serve at least two separable and distinct functions.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9403541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33441916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of cardiac function in rat endovascular perforation model of subarachnoid hemorrhage; A model of subarachnoid hemorrhage-induced cardiac dysfunction.","authors":"Masahito Munakata,&nbsp;Hideaki Kanazawa,&nbsp;Kensuke Kimura,&nbsp;Takahide Arai,&nbsp;Hiroaki Sukegawa,&nbsp;Keiichi Fukuda","doi":"10.3389/fnsyn.2022.919998","DOIUrl":"https://doi.org/10.3389/fnsyn.2022.919998","url":null,"abstract":"<p><p>Although the association between cardiac dysfunction and subarachnoid hemorrhage (SAH) has been recognized, its precise underlying mechanism remains unknown. Furthermore, no suitable animal models are available to study this association. Here, we established an appropriate animal model of SAH-induced cardiac dysfunction and elucidated its mechanism. In this rat model, contrast-enhanced computed tomography of the brain confirmed successful induction of SAH. Electrocardiography detected abnormalities in 55% of the experimental animals, while echocardiography indicated cardiac dysfunction in 30% of them. Further evaluation of left ventriculography confirmed cardiac dysfunction, which was transient and recovered over time. Additionally, in this SAH model, the expression of the acute phase reaction protein, proto-oncogene c-Fos increased in the paraventricular hypothalamic nucleus (PVN), the sympathetic nerve center of the brain. Polymerase chain reaction analysis revealed that the SAH model with cardiac dysfunction had higher levels of the macrophage-associated chemokine (C-X-C motif) ligand 1 (CXCL-1) and chemokine (C-C motif) ligand 2 (CCL-2) than the SAH model without cardiac dysfunction. Our results suggested that SAH caused inflammation and macrophage activation in the PVN, leading to sympathetic hyperexcitability that might cause cardiac dysfunction directly and indirectly. This animal model may represent a powerful tool to investigate the mechanisms of the brain-heart pathway.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2022-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9396209/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33437879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential modulation of collybistin conformational dynamics by the closely related GTPases Cdc42 and TC10.","authors":"Nasir Imam, Susobhan Choudhury, Katrin G Heinze, Hermann Schindelin","doi":"10.3389/fnsyn.2022.959875","DOIUrl":"10.3389/fnsyn.2022.959875","url":null,"abstract":"<p><p>Interneuronal synaptic transmission relies on the proper spatial organization of presynaptic neurotransmitter release and its reception on the postsynaptic side by cognate neurotransmitter receptors. Neurotransmitter receptors are incorporated into and arranged within the plasma membrane with the assistance of scaffolding and adaptor proteins. At inhibitory GABAergic postsynapses, collybistin, a neuronal adaptor protein, recruits the scaffolding protein gephyrin and interacts with various neuronal factors including cell adhesion proteins of the neuroligin family, the GABA _<i>A</i> receptor α2-subunit and the closely related small GTPases Cdc42 and TC10 (RhoQ). Most collybistin splice variants harbor an N-terminal SH3 domain and exist in an autoinhibited/closed state. Cdc42 and TC10, despite sharing 67.4% amino acid sequence identity, interact differently with collybistin. Here, we delineate the molecular basis of the collybistin conformational activation induced by TC10 with the aid of recently developed collybistin FRET sensors. Time-resolved fluorescence-based FRET measurements reveal that TC10 binds to closed/inactive collybistin leading to relief of its autoinhibition, contrary to Cdc42, which only interacts with collybistin when forced into an open state by the introduction of mutations destabilizing the closed state of collybistin. Taken together, our data describe a TC10-driven signaling mechanism in which collybistin switches from its autoinhibited closed state to an open/active state.</p>","PeriodicalId":12650,"journal":{"name":"Frontiers in Synaptic Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9386560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40713863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}