Activity-dependent development of chandelier cell cortical integration and connectivity

 描述（由申请人提供）：在哺乳动物新皮层中，GABA能中间神经元由调节神经回路平衡和功能组织的不同细胞类型组成。然而，不同的GABA细胞类型的发育组装成抑制电路仍然知之甚少。例如，枝形吊灯细胞（ChC）特异性地支配锥体神经元（PyN）在其轴突起始段（AIS）（动作电位起始部位）处，并且限定高度定型的电路模块。ChC在胚胎妊娠晚期被指定，并通过长距离迁移部署到特定的皮质层。然而，它仍然是未知的，在到达皮层，ChCs的密度和分布是如何调节的第一步，建立其电路连接。我们已经建立了一个实验系统来跟踪ChCs的发展轨迹，包括他们的皮层回路整合。在这里，我将研究的发展和活动调节机制，指导ChCs在视觉皮层，特别是在初级（V1）和更高（V2）视觉区之间的边界区域的适当分布。我发现，在成熟皮层中，第2层（L2）ChCs的密度在V1/V2边界处比邻近的V1和V2适当地减少一半。在出生后，在出生后第7天（P7）到达L2时，ChC均匀分布在V1和V2上，但随后在P7-P14之间经历大量凋亡，在边界区域细胞死亡显著增加。我表明，这种特定的细胞修剪的增加是由轴突和活动的胼胝体投射神经元（CPNs）在对侧皮层。重要的是，我发现在睁眼前视网膜活动调节对侧V1/V2边界的ChCs密度。我推测，在V1/V2边界的ChCs的密度和电路集成的调节，通过跨半球胼胝体神经元的输入塑造出生后早期的视网膜活动。我建议首先确定 在ChC电路整合期间，从CPN到ChCs的功能性长程输入，并研究CPN输入在调节ChCs在V1/V2边界的存活中的作用。然后，我将研究如何增加的ChC密度在V1/V2边界的影响，被认为是介导的CPNs的视觉反应特性的半球间同步。最后，我将研究相关视网膜活动在调节ChC分布中的作用，重要的是，建立视网膜活动如何通过CPN活动模式调节ChC存活之间的联系。这些研究将首次证明一个强大的抑制模块的组装是如何通过锥体输入由外周活动模式调节的。这将有助于理解皮层电路组装以及神经发育障碍的异常电路布线机制。

 DESCRIPTION (provided by applicant): In mammalian neocortex, GABAergic interneurons consist of diverse cell types which regulate the balance and functional organization of neural circuitry. However, the developmental assembly of distinct GABA cell types into inhibitory circuitry remains poorly understood. For example, the chandelier cells (ChCs) specifically innervate pyramidal neurons (PyNs) at their axon initial segment (AIS), the site of action potential initiation, and defines a highly stereotyped circuit module. ChCs are specified at late embryonic gestation and are deployed to specific cortical layers through long range migration. However, it remains unknown how, upon reaching the cortex, the density and distribution of ChCs are regulated as a first step toward establishing their circuit connectivity. We have established an experimental system to track the developmental trajectory of ChCs, including their cortical circuit integration. Here I will study the developmental and activity-regulated mechanisms that guide the proper distribution of ChCs in the visual cortex, specifically at the border region between primary (V1) and higher (V2) visual areas. I have found that the density of layer 2 (L2) ChCs in mature cortex is reduced by half at V1/V2 border compared with neighboring V1 and V2 proper. During postnatal period, upon reaching L2 by postnatal day 7 (P7), ChCs are evenly distributed across V1 and V2, but then undergo massive apoptosis between P7-P14, with significantly more enhanced cell death at border region. I showed that this specific increase of cell pruning is regulated by axons and activity of callosal projection neurons (CPNs) in the contralateral cortex. Importantly, I found that retinal activity before eye opening regulates the density of ChCs at contralateral V1/V2 border. I hypothesize that the density and circuit integration of ChCs at V1/V2 border are regulated by trans-hemispheric callosal neuron inputs shaped by early postnatal retinal activity. I propose to first determine the functional long-range input from CPNs to ChCs during the period of ChC circuit integration, and investigate the role of CPN input in regulating the survival of ChCs at the V1/V2 border. I will then examine how an increase of ChC density at V1/V2 border impacts the interhemispheric synchronization of visual response properties, thought to be mediated by CPNs. Lastly, I will examine the role of correlated retinal activity in regulating ChC distribution, and importantly, establish the link between how retinal activity regulates ChC survival through CPN activity pattern. These studies will represent the first demonstration of how the assembly of a powerful inhibitory module is regulated by peripheral activity pattern through pyramidal inputs. This will shed light on understanding cortical circuit assembly as well as on mechanisms of aberrant circuit wiring underlying neurodevelopmental disorders.