Functions of electrical synapses in inhibitory networks

描述(申请人提供)：这个项目将研究哺乳动物前脑抑制回路中的电突触的功能。“电突触”是连接神经元的缝隙连接，它们是快速、双向的交流途径。关于哺乳动物电突触的基本生物物理性质、它们的位置以及它们对缝隙连接蛋白Cx36(Cx36)的依赖，人们已经知道了相当多。缝隙连接可以强烈地影响成对和小群神经元的动作电位的时间、相位、同步性、概率和速率，但我们仍然不知道电突触如何对更大的网络功能做出贡献。前脑回路的复杂性长期以来一直是一个障碍，但现在可以利用强大的新基因和光学工具来解决这些问题。值得注意的是，在成熟的丘脑和新皮质中，电突触几乎只出现在GABA能神经元之间。这些连接是非常特殊的；它们通常连接皮质中同一亚型的抑制性神经元，而成熟前脑中的兴奋细胞很少表达它们。这项研究将集中于连接丘脑(特别是体感丘脑网状核)的抑制性神经元和新皮质(桶状皮质)几种亚型中间神经元的电突触的作用。有三个具体目标。第一个是确定电突触在丘脑皮质网络活动中的作用，特别是在体外和体内研究的慢(β，θ)和快(伽马)网络振荡。我们将使用电生理学，选择性地从皮质和丘脑抑制细胞亚型中删除Cx36，以及光遗传学来控制特定的神经元和轴突通路。第二个目的是验证这一假设，即电突触在丘脑和皮质丘脑通路激活的强大前馈抑制电路中发挥重要作用。第三个目标是确定TRN和新皮质的躯体感觉节段中缝隙连接耦合网络的空间和细胞类型特定的组织。抑制回路是普遍存在的，对所有感觉、运动和认知功能都是必不可少的；电突触是抑制回路中无处不在的组成部分。抑制异常与多种神经、精神和发育障碍有关，缝隙连接基因突变与癫痫和其他神经功能障碍有关。我们的研究将有助于阐明电突触在前脑抑制系统中的相关性和功能。

DESCRIPTION (provided by applicant): This project will investigate the functions of electrical synapses within inhibitory circuits of the mammalian forebrain. "Electrical synapses" are gap junctions that interconnect neurons, and they serve as rapid, bidirectional communication pathways. A considerable amount is known about the basic biophysical properties of mammalian electrical synapses, their locations, and their dependence on the gap junction protein connexin36 (Cx36). Gap junctions can strongly influence the timing, phase, synchrony, probability, and rate of action potentials in pairs and small groups of neurons, yet we still do no know how electrical synapses contribute to larger network functions. The complexity of forebrain circuits has long been an impediment, but powerful new genetic and optical tools can now be brought to bear on these issues. Remarkably, in the mature thalamus and neocortex electrical synapses occur almost exclusively between GABAergic neurons. These junctions are quite specific; they usually interconnect inhibitory neurons of the same subtype in the cortex, and excitatory cells in the mature forebrain rarely express them. This investigation will focus on the roles of electrical synapses that interconnect inhibitory neurons of the thalamus (specifically in the somatosensory thalamic reticular nucleus, TRN), and several subtypes of interneurons in the neocortex (barrel cortex). There are three specific aims. The first is to determine the roles o electrical synapses in thalamocortical network activity, specifically slow (delta, theta) and fast (gamma) network oscillations studied in vitro and in vivo. We will use electrophysiology, selective deletion of Cx36 from subtypes of cortical and thalamic inhibitory cells, and optogenetics to control specific neurons and axonal pathways. The second aim is to test the hypothesis that electrical synapses play an important role in the powerful feedforward inhibitory circuits activated by both thalamocortical and corticothalamic pathways. The third aim is to define the spatial and cell type-specific organization of gap junction-coupled networks in somatosensory segments of the TRN and neocortex. Inhibitory circuits are universal, and essential for all sensory, motor, and cognitive functions; electrical synapses are ubiquitous components of inhibitory circuits. Abnormalities of inhibition are implicated in a wide variety of neurological, psychiatric, and developmental disorders, and mutations in gap junction genes are associated with epilepsy and other neurological dysfunctions. Our investigation will help to clarify the relevance and functions of electrical synapses in inhibitory systems of the forebrain.