Activity dependent integration of chandelier cells during cortical circuit assembly

摘要 尽管在了解主要类别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 适当的密度并集成到皮质电路中仍有待探索。枝形吊灯细胞 (ChC) 代表一种真正的中间神经元类型，专门支配轴突处的锥体细胞 (PC) 初始段，动作电位起始部位。使用最先进的小鼠遗传方法，我们 建立了一个强大的实验系统来研究定型 ChC-PC 电路的组装 模块。我们之前发现ChC命运是由内侧的祖细胞指定的 晚期神经发生期间的神经节隆起。一旦通过血统和出生时间指定 机制，年轻的 ChC 似乎被赋予了细胞内在的程序，指导它们迁移到 实现明显的层状沉降。重要的是，成熟皮质中的 ChC 介导定向抑制 由投影目标定义的 PC 整体之间的控制。发育机制 达到如此精致的特异性还是未知的。在本提案中，我们研究了以下一般假设： 活性依赖性 ChC 凋亡有助于塑造 ChC 和 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。 基于大量证据，我们的总体假设是 ChC 密度和连接特异性 初级和次级视觉皮层（V1 和外侧 V2）之间的边界区域受以下因素调节 对侧和同侧胼胝体 PC 输入 (CALPC)，由视网膜活动协调；和 ChCs 对 CALPCs 的神经支配减少可能会促进双边交流，从而整合内部 半球视觉反应特性。我们首先来描述ChC-PC的发展特点 V1/V2 边界区域的连接（目标 1）。然后我们将确定对侧 CALPC 轴突和 活性调节边界的 ChC 密度 (Aim2)。我们将进一步确定视网膜活动如何 调节 V1/V2 边界的 ChC 密度 (Aim3)。最后，我们将研究 ChC 在调节中的作用 两个视觉半球视觉反应特性的双边同步（目标4）。我们的研究 将为阐明遗传和活动依赖性机制如何协调提供异常清晰的信息 在哺乳动物大脑中塑造具有细胞类型分辨率的电路布线。这些研究将揭示新颖的 神经元修剪的活动依赖性机制，形成高度特异性的电路连接和 可能对神经发育障碍（例如自闭症谱系障碍）和 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.