Activity dependent integration of chandelier cells during cortical circuit assembly

摘要 尽管在理解主要类群的胚胎起源和迁徙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 适当的密度和整合到大脑皮层环路中仍未被探索。枝形吊灯单元 (CHC)代表了一种真正的中间神经元类型，它特异性地支配轴突上的锥体细胞(PC) 起始段，动作电位的起始点。使用最先进的小鼠遗传方法，我们 建立了一个用于研究千篇一律的CHC-PC电路组装的可靠的实验系统 模块。我们之前已经发现，CHC的命运是从医学的祖先那里指定的 神经发生后期的神经节突起。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，成熟皮质中的CHC介导定向抑制 由投影目标定义的PC合奏之间的控制。的发育机制 达到如此精致的专一性是未知的。在这个提议中，我们检验了普遍的假设 活性依赖的CHC细胞凋亡有助于塑造CHC和CHC之间的选择性连接 PC在视觉皮质，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密度和连接专一性在 初级和次级视觉皮质(V1和外侧V2)之间的交界区由 与视网膜活动相协调的对侧和内侧胼胝体PC输入(CalPC)； CHC对CALPC的神经支配减少可能会促进双边沟通，整合了 大脑半球视觉反应特性。我们将首先描述CHC-PC的发展 V1/V2边界区域(Aim1)的连通性。然后我们将确定对侧CalPC轴突和 活动调节边界的CHC密度(AIM2)。我们将进一步确定视网膜活动如何 调节V1/V2交界处的CHC浓度(Aim3)。最后，我们将研究社区卫生委员会在监管方面的作用。 双侧视觉反应特性在两个视觉半球的同步性(Aim4)。我们的研究 将为阐明遗传和活动依赖机制如何协调提供了异常清晰的信息 来塑造哺乳动物大脑中具有细胞类型分辨率的电路布线。这些研究将揭示新奇的 神经元修剪的活动依赖机制，形成高度特异性的电路连接和 可能与神经发育障碍有关，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.