Molecular mechanisms underlying cortical interneuron synaptic specificity

皮质中间神经元突触特异性的分子机制

基本信息

批准号：
10096397
负责人：
HIROKI TANIGUCHI
金额：
$ 48.25万
依托单位：
MAX PLANCK FLORIDA CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-15 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10096397
关键词：
Address Adhesions Automobile Driving Axon Binding Biological Assay Brain Brain Diseases Brain Injuries Cells Data Development Disease Ectopic Expression Electroporation Ensure Epilepsy Equilibrium Etiology Functional disorder Gene Expression Gene Transfer Generations Goals Individual Interneurons Knock-out Knockout Mice Location Medial Mediating Modeling Molecular Morphology Mus Neurons Phenotype Physiology Play Prefrontal Cortex Property Proteins Role Schizophrenia Series Shapes Signal Transduction Specificity Synapses System Testing Therapeutic Transplantation Viral Genes autism spectrum disorder base cell type experimental study genome editing hippocampal pyramidal neuron in vivo insight malformation mouse genetics neurofascin novel postsynaptic neurons presynaptic receptor repaired stereotypy success synaptogenesis

Address Adhesions Automobile Driving Axon Binding Biological Assay Brain Brain Diseases Brain Injuries Cells Data Development Disease Ectopic Expression Electroporation Ensure Epilepsy Equilibrium Etiology Functional disorder Gene Expression Gene Transfer Generations Goals Individual Interneurons Knock-out Knockout Mice Location Medial Mediating Modeling Molecular Morphology Mus Neurons Phenotype Physiology Play Prefrontal Cortex Property Proteins Role Schizophrenia Series Shapes Signal Transduction Specificity Synapses System Testing Therapeutic Transplantation Viral Genes autism spectrum disorder base cell type experimental study genome editing hippocampal pyramidal neuron in vivo insight malformation mouse genetics neurofascin novel postsynaptic neurons presynaptic receptor repaired stereotypy success synaptogenesis

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项目摘要

Project Summary/Abstract Cortical inhibitory GABAergic interneurons (INs), which develop intricate local circuits, critically regulate higher- order brain functions by balancing and shaping neuronal activity. Consistent with its indispensable role in normal brain functions, malformation/malfunction of the inhibitory system is implicated in a wide array of brain disorders such as schizophrenia, autism, and epilepsy. Despite their importance, the molecular mechanisms underlying the wiring of IN local circuits remain largely unknown. Cortical INs comprise diverse cell types that are defined by morphology, physiology, and gene expression. Notably, different IN subtypes also show distinct synaptic specificity at laminar/cellular as well as subcellular levels. Although subtype-specific synaptic connectivity is considered a critical property of INs to ensure functional diversity of the inhibitory system, the molecular mechanisms underlying IN synaptic specificity remains poorly understood. The objective of this proposal is to determine the molecular mechanisms by which IN subtypes establish layer/cell type- and subcellular domain-specific synapses. To achieve this goal, we will perform a series of experiments using chandelier cells (ChCs), which exclusively innervate axon initial segments (AISs) of layer-specific pyramidal neurons (PNs). The ChC is known to critically regulate PN spike generation and has been implicated in schizophrenia and epilepsy. Besides their functional significance, the stereotypy of their synaptic organization make ChCs an attractive model to study the molecular mechanisms for IN synaptic specificity. Our preliminary data has shown that: (1) IgSF11 proteins that are known to bind with each other are expressed in both ChCs and layer-specific target PNs, (2) Gldn proteins that are known to bind to AIS-enriched proteins, NF186, are preferentially expressed in ChCs, (3) IgSF11 in ChCs plays an essential role in their presynaptic development, (4) Gldn and NF186 appear to play a role in initiating ChC synapses, and (5) IgSF11 that is free from the Gldn-NF186 system appears not to induce ChC synapses. Based on our findings, we propose to test the hypothesis that the layer-specific synaptogenic action and the subcellular domain-specific recognition mediated through IgSF11 homophilic interactions and Gldn-NF186 interactions, respectively, cooperatively determine ChC synaptic specificity. We will pursue the following specific aims to test our hypothesis. In Aim 1, we will determine the role of the IgSF11 homophilic interaction between pre- and postsynaptic neurons in layer-specific synapse formation by ChCs. In Aim 2, we will determine the role of Gldn and NF186 in ChC synapse formation on AISs. In Aim 3, we will determine the regulatory role of NF186/Gldn in gating IgSF11 signaling to induce ChC presynaptic boutons at AISs. Upon completion of this study, we will gain not only important insights into molecular mechanisms for IN wiring but also a clue to developing therapeutic strategies to functionally repair disordered/damaged brains.

项目摘要/摘要皮质抑制性GABA能中间神经元（INS），会产生复杂的局部电路，严重调节较高的通过平衡和塑造神经元活性来顺序脑功能。与其必不可少的作用正常的大脑功能，抑制系统的畸形/故障与广泛的大脑有关精神分裂症，自闭症和癫痫等疾病。尽管它们的重要性，但分子机制本地电路中的接线的基础在很大程度上是未知的。皮质INS包括各种细胞类型由形态学，生理和基因表达定义。值得注意的是，亚型的不同也显示出不同的层状/细胞以及亚细胞水平的突触特异性。虽然亚型特异性突触连通性被认为是INS的关键特性，以确保抑制系统的功能多样性，即突触特异性上基于的分子机制仍然很少理解。这个目的建议是确定在亚型中建立层/细胞类型的分子机制和亚细胞特异性突触。为了实现这一目标，我们将执行一系列实验使用吊灯细胞（CHC），该单元仅支配轴突初始段（AISS）。锥体神经元（PNS）。众所周知，CHC严重调节PN峰值的生成，并已被牵涉到在精神分裂症和癫痫病中。除了其功能意义，其突触的刻板印象组织使CHC成为研究突触特异性的分子机制的有吸引力的模型。我们的初步数据表明：（1）已知彼此结合的IGSF11蛋白在CHC和层特异性靶PN中，（2）GLDN蛋白已知与AIS富集蛋白结合， NF186优先在CHC中表达，（3）CHC中的IGSF11在其突触前起着至关重要的作用开发，（4）GLDN和NF186似乎在启动CHC突触中起作用，（5）IGSF11是免费的从GLDN-NF186系统中，似乎没有诱导CHC突触。根据我们的发现，我们建议测试层特异性突触作用和亚细胞特异性识别的假设分别通过IGSF11均电相互作用和GLDN-NF186相互作用进行介导确定CHC突触特异性。我们将追求以下特定目标来检验我们的假设。在AIM 1中，我们将确定前突触神经元与突触后神经元之间IGSF11均电相互作用的作用 CHCS的层特异性突触形成。在AIM 2中，我们将确定GLDN和NF186在CHC中的作用在艾斯（Aiss）上的突触形成。在AIM 3中，我们将确定NF186/GLDN在门控IGSF11中的调节作用信号传导在AISS诱导CHC前胸肌。完成这项研究后，我们不仅会获得对接线的分子机制的重要见解，也是制定治疗策略的线索在功能上修复无序/受损的大脑。