Role of histone deacetylases in the development of GABAergic interneuron connectivity and function

组蛋白脱乙酰酶在 GABA 能中间神经元连接和功能发育中的作用

• 批准号: RGPIN-2016-06067
• 负责人: DiCristo, Graziella
• 金额: $ 3.21万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688809
• 关键词: Role; histone; deacetylases; development; GABAergic

GABAergic neurons form an important subset of the neuronal population in the brain, which powerfully control the dynamics of brain circuits. In addition, they strongly regulate brain development by modulating several processes including experience-dependent neuronal wiring. The complexity of brain circuitry and the non-homogeneity of the GABAergic cell population has so far made the study of how these neurons develop and form synaptic connections very difficult. We have recently developed techniques to label and manipulate parvalbumin positive GABAergic cells (PV cells), which constitute the most numerous types of cortical GABAergic neurons. PV cells form dense axonal arborisations that innervate hundreds of target neurons, each with multiple, clustered synapses onto their soma and proximal dendrites. Such precise subcellular location of PV cell synapses, in conjunction with their striking ability to fire sustained trains of brief action potentials at remarkably high frequency, allows them to powerfully control the output of their target cells and influence large network activities in the brain. My long-term goal is to understand the mechanisms underlying the formation of cortical PV cell connectivity and how they modulate experience-dependent cortical plasticity in the young and adult brain. ******Molecular mechanisms involved in synapse formation and strengthening include the activation and repression of specific genes by stable epigenetic modifications. Chromatin remodeling, especially through histone-tail acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. In particular, Histones Deacetylase 2 (HDAC2) has been shown to regulate excitatory synapse formation and plasticity. Interestingly, HDAC2 binding to chromatic is strongly regulated by the brain-derived neurotrophic factor BDNF, which is one of the most powerful factors promoting PV cell synapse formation. Here, we propose to use a unique combination of single-cell genetics, conditional knockout mice, high-resolution imaging, mouse behavioural testing, ex vivo and in vivo electrophysiology to investigate the role of HDAC2 in PV cell circuit development. Our working hypothesis is that HDAC2 is a critical molecular determinant of the postnatal development of PV cell circuits and that, in its absence, PV cell connectivity and function remain immature. ******The proposed experiments will shed light on the epigenetic mechanisms controlling the development of cortical PV cell connectivity and, in turn, developmental plasticity. The multidisciplinary core of the proposed approaches and the use of in vitro and in vivo experimental models will provide excellent training opportunities for HQPs at both the graduate and undergraduate levels.**

GABA能神经元是脑内神经元的重要组成部分，对脑回路的动力学起着重要的控制作用。此外，它们通过调节几个过程，包括经验依赖性神经元布线，强烈调节大脑发育。大脑回路的复杂性和GABA能细胞群的非同质性使得迄今为止对这些神经元如何发育和形成突触连接的研究非常困难。我们最近开发了标记和操纵小清蛋白阳性GABA能细胞（PV细胞）的技术，PV细胞构成了最多类型的皮质GABA能神经元。PV细胞形成密集的轴突分支，支配数百个靶神经元，每个靶神经元在其索马和近端树突上具有多个成簇的突触。PV细胞突触的这种精确的亚细胞定位，结合它们以非常高的频率发射持续的短暂动作电位序列的惊人能力，使它们能够有力地控制其靶细胞的输出并影响大脑中的大型网络活动。我的长期目标是了解皮质PV细胞连接形成的潜在机制，以及它们如何调节年轻和成年大脑中经验依赖性的皮质可塑性。** 参与突触形成和加强的分子机制包括通过稳定的表观遗传修饰激活和抑制特定基因。染色质重塑，特别是通过组蛋白尾部乙酰化，改变了紧凑的染色质结构，改变了DNA的可及性的调节蛋白，正在成为一个基本的机制，调节基因的表达。特别地，组蛋白脱乙酰酶2（HDAC 2）已显示出调节兴奋性突触形成和可塑性。有趣的是，HDAC2与染色质的结合受到脑源性神经营养因子BDNF的强烈调节，BDNF是促进PV细胞突触形成的最有力的因子之一。 在这里，我们建议使用单细胞遗传学，条件性基因敲除小鼠，高分辨率成像，小鼠行为测试，离体和体内电生理学的独特组合来研究HDAC2在PV电池电路开发中的作用。我们的工作假设是HDAC2是PV细胞回路出生后发育的关键分子决定因素，并且在其缺失的情况下，PV细胞连接和功能仍然不成熟。** 拟议的实验将揭示控制皮层PV细胞连接发育的表观遗传机制，进而揭示发育可塑性。所提出的方法的多学科核心以及体外和体内实验模型的使用将为研究生和本科生水平的HQP提供极好的培训机会。