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:
    10523360
  • 负责人:
  • 金额:
    $ 35.66万
  • 依托单位:
  • 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 2025-12-31
  • 项目状态:
    未结题

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.
项目总结/摘要 皮层抑制性GABA能中间神经元(INs),发展复杂的局部回路,关键地调节较高的 通过平衡和塑造神经元活动来调整大脑功能。与其在以下方面不可或缺的作用相一致: 正常的脑功能,抑制系统的畸形/功能障碍涉及广泛的脑功能障碍, 精神分裂症、自闭症和癫痫等疾病。尽管它们很重要, 在IN本地电路的布线的基础上仍然很大程度上未知。皮质IN包括不同的细胞类型, 由形态学、生理学和基因表达来定义。值得注意的是,不同的IN亚型也表现出不同的 突触特异性在层/细胞以及亚细胞水平。虽然亚型特异性突触 连接性被认为是确保抑制系统功能多样性的IN的关键属性, IN突触特异性的分子机制仍然知之甚少。的目的 建议是确定IN亚型建立层/细胞类型的分子机制- 和亚细胞区域特异性突触。为了实现这一目标,我们将进行一系列的实验 使用枝形吊灯细胞(ChCs),其专门支配层特异性的轴突起始段(AIS), 锥体神经元(PNs)。已知ChC对PN尖峰的产生起关键性调节作用, 精神分裂症和癫痫症除了它们的功能意义外,它们的突触的刻板性 ChCs的组织结构使其成为研究IN突触特异性分子机制的一个有吸引力的模型。 我们的初步数据表明:(1)已知相互结合的IgSF 11蛋白表达为 在ChC和层特异性靶向PN中,(2)已知与AIS富集蛋白结合Gldn蛋白, (3)IgSF 11在ChCs的突触前表达中起重要作用, (4)Gldn和NF 186似乎在启动ChC突触中起作用,以及(5)IgSF 11是游离的, 来自Gldn-NF 186系统的Gdn-NF 186似乎不诱导ChC突触。根据我们的发现,我们建议测试 层特异性突触发生作用和亚细胞结构域特异性识别 分别通过IgSF 11同嗜性相互作用和Gldn-NF 186相互作用协同介导, 确定ChC突触特异性。我们将追求以下具体目标来检验我们的假设。在目标1中, 我们将确定突触前和突触后神经元之间IgSF 11嗜同性相互作用在 ChC的层特异性突触形成。在目的2中,我们将确定Gldn和NF 186在ChC中的作用。 AIS上的突触形成。在目标3中,我们将确定NF 186/Gldn在门控IgSF 11中的调节作用。 信号传导以诱导AIS处的ChC突触前终扣。这项研究完成后,我们不仅可以 对IN布线的分子机制的重要见解,也是开发治疗策略的线索 功能性修复紊乱/受损的大脑。

项目成果

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HIROKI TANIGUCHI其他文献

HIROKI TANIGUCHI的其他文献

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{{ truncateString('HIROKI TANIGUCHI', 18)}}的其他基金

The role of acetylcholine signaling in the axonal wiring of cortical interneurons
乙酰胆碱信号在皮质中间神经元轴突布线中的作用
  • 批准号:
    10578784
  • 财政年份:
    2022
  • 资助金额:
    $ 35.66万
  • 项目类别:
Wiring and developmental principles of inhibitory neocortical circuits
抑制性新皮质回路的布线和发育原理
  • 批准号:
    10478363
  • 财政年份:
    2022
  • 资助金额:
    $ 35.66万
  • 项目类别:
The role of acetylcholine signaling in the axonal wiring of cortical interneurons
乙酰胆碱信号在皮质中间神经元轴突布线中的作用
  • 批准号:
    10372840
  • 财政年份:
    2022
  • 资助金额:
    $ 35.66万
  • 项目类别:
Molecular mechanisms underlying cortical interneuron synaptic specificity
皮质中间神经元突触特异性的分子机制
  • 批准号:
    10558671
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:
Molecular mechanisms underlying cortical interneuron synaptic specificity
皮质中间神经元突触特异性的分子机制
  • 批准号:
    10096397
  • 财政年份:
    2021
  • 资助金额:
    $ 35.66万
  • 项目类别:

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