Functions of electrical synapses in inhibitory networks

项目总结/摘要 本计画将探讨哺乳动物抑制回路中的电突触功能 前脑“电突触”是连接神经元的间隙连接，它们作为快速， 双向通信路径。关于基本的生物物理学， 哺乳动物电突触的性质、位置及其对差距连接的依赖性 连接蛋白36（Cx 36）。缝隙连接可以强烈影响时间，相位，同步性，概率， 以及成对和小群神经元的动作电位的速率，但我们仍然不知道电 突触有助于更大的网络功能。前脑回路的复杂性长期以来一直是 虽然目前还存在一些障碍，但现在可以利用强大的新遗传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层中，电突触几乎只发生在 GABA能神经元。这些连接是非常特殊的，它们通常连接抑制性神经元， 皮质中的相同亚型，成熟前脑中的兴奋性细胞很少表达它们。这 研究将集中在电突触的作用，互连抑制性神经元的， 丘脑（特别是在体感丘脑网状核，TRN），和几个亚型的 新皮质（barrel cortex）。有三个具体目标。第一，确定 电突触在丘脑皮层网络活动中的作用，特别是慢（δ，θ）和快 （伽马）网络振荡研究在体外和体内。我们将使用电生理学，选择性删除 从皮质和丘脑抑制性细胞亚型中分离Cx 36，以及控制特定神经元的光遗传学 和轴突通路。第二个目的是验证电突触在神经元的活动中起重要作用的假设。 在由丘脑皮质和皮质丘脑激活的强大前馈抑制回路中的作用 途径。第三个目的是确定间隙连接偶联的空间和细胞类型特异性组织， TRN和新皮层的躯体感觉部分的网络。 抑制回路是普遍的，对所有感觉、运动和认知功能都是必不可少的; 突触是抑制回路的普遍存在的组成部分。抑制的缺失与一种 各种神经、精神和发育障碍，以及间隙连接基因突变 与癫痫和其他神经功能障碍有关。我们的调查将有助于澄清 前脑抑制系统中电突触的相关性和功能。

PROJECT SUMMARY/ABSTRACT 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 not 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 of 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.