Activity dependent integration of chandelier cells during cortical circuit assembly

摘要 尽管在了解主要种类的胚胎起源和迁移方面取得了重大进展， 皮质GABA能中间神经元，不同的中间神经元类型如何部署到皮质层， 适当的密度，并整合到皮层电路仍然是未知的。吊灯的格子 ChCs是一种真正的中间神经元类型，其特异性地支配轴突上的锥体细胞（PC）。 起始段，即动作电位起始部位。使用最先进的小鼠遗传学方法，我们 建立了一个用于研究定型ChC-PC电路组装的实验系统 module.我们以前已经发现，ChC的命运是由中膜细胞的祖细胞指定的。 神经节隆起在晚期神经发生。一旦通过血统和出生时间指定 年轻的ChCs似乎被赋予了细胞内在的程序，引导它们迁移到 实现明显的层状沉降。重要的是，成熟皮层中的ChC介导定向抑制性， 控制由投影目标定义的PC集合。发展机制 达到如此精确的特异性是未知的。在这个提议中，我们研究了一般假设， 活性依赖性ChC凋亡有助于塑造ChC之间的选择性连接， 视觉皮层中的PC，我们的目标是将发育机制与功能意义联系起来。 基于大量的证据，我们的总体假设是，ChC密度和连接特异性在 初级和次级视觉皮层之间的边界区域（V1和外侧V2）由以下调节： 对侧和同侧胼胝体PC输入（CALPC），其由视网膜活动协调;以及 ChCs对CALPCs的神经支配减少，可能有助于整合细胞间的双向交流。 半球视觉反应特性。我们将首先描述ChC-PC的发展特点 V1/V2边界区域（Aim 1）的连通性。然后，我们将确定对侧CALPC轴突和 活性调节边界处的ChC密度（Aim 2）。我们将进一步确定视网膜活动 调节V1/V2界ChC密度（Aim 3）。最后，我们将研究ChCs在调节 两个视觉半球中视觉反应特性的双侧同步（Aim 4）。我们的研究 将提供特殊的清晰度，阐明遗传和活动依赖机制如何协调 在哺乳动物的大脑中，用细胞类型的分辨率来塑造电路布线。这些研究将揭示新的 神经元修剪的活动依赖机制，形成高度特异性的电路连接， 可能与神经发育障碍有关，如自闭症谱系障碍， 精神分裂症

ABSTRACT Despite major progress in understanding the embryonic origin and migration of major classes of cortical GABAergic interneurons, how distinct interneuron types are deployed to cortical layers with appropriate density and are integrated into cortical circuits remains unexplored. The chandelier cells (ChCs) represent a bona fide interneuron type that specifically innervates pyramidal cells (PCs) at axon initial segment, the site of action potential initiation. Using state-of-the-art mouse genetic approaches, we have established a robust experiment system for studying the assembly of a stereotyped ChC-PC circuit module. We have previously discovered that ChC fate is specified from progenitors of the medial ganglionic eminence during late neurogenesis. Once specified through lineage and birth timing mechanisms, young ChCs appear endowed with cell-intrinsic programs that guide their migration to achieve distinct laminar settlement. Importantly, ChCs in mature cortex mediate directional inhibitory control between PC ensembles defined by projection targets. The developmental mechanisms to achieve such exquisite specificity is unknown. In this proposal, we examine the general hypothesis that activity-dependent ChC apoptosis contributes to sculpting the selective connectivity between ChCs and PCs in the visual cortex, where we aim to link development mechanisms to functional significance. Based on substantial evidence, our Overall Hypothesis is that ChC density and connection specificity at the border region between primary and secondary visual cortex (V1 and lateral V2) is regulated by contra- and ipsi-lateral callosal PC inputs (CALPC), which are coordinated by retinal activities; and reduced innervation of CALPCs by ChCs may facilitate bilateral communication that integrates Inter- hemispheric visual response properties. We will first characterize the development of ChC-PC connectivity at V1/V2 border region (Aim1). We will then determine how contralateral CALPC axons and activity regulate ChC density at the border (Aim2). We will further determine how retinal activities regulate ChC density at V1/V2 border (Aim3). Finally, we will examine the role of ChCs in regulating bilateral synchronization of visual response properties in the two visual hemispheres (Aim4). Our study will provide exceptional clarity in elucidating how genetic and activity dependent mechanisms coordinate to shape circuit wiring with cell type resolution in the mammalian brain. These studies will reveal novel activity-dependent mechanisms of neuronal pruning that shape highly specific circuit connectivity and may have implications in neurodevelopmental disorders such as autism spectrum disorders and schizophrenia.