Source data - Cadherins orchestrate specific patterns of perisomatic inhibition onto distinct pyramidal cell populations

GABAergic interneurons were long thought to regulate excitatory networks by establishing unselective connections onto diverse populations of pyramidal cells, but recent studies demonstrate the existence of a cell type-specific inhibitory connectome. How and when interneurons establish precise connectivity patterns among intermingled populations of excitatory neurons remains enigmatic. Here, we explore the molecular mechanisms orchestrating the emergence of cell type-specific inhibition in the mouse cerebral cortex. We demonstrate that layer 5 intra- (L5 IT) and extra-telencephalic (L5 ET) neurons express unique transcriptional programs, allowing them to shape parvalbumin- (PV+) and cholecystokynine-positive (CCK+) interneuron wiring. We identified <i>Cdh12</i><i> </i>and <i>Cdh13</i>, two cadherin superfamily members, as underpinnings of cell type- and input-specific inhibitory patterns of L5 pyramidal cell populations. Multiplex monosynaptic tracing revealed a minimal overlap between L5 IT and L5 ET presynaptic inhibitory networks and suggests that different PV+ basket cell populations innervate distinct L5 pyramidal cell types. Altogether, our work unravels the contribution of cadherins in shaping cell type-specific cortical interneuron wiring.

GABA能中间神经元（GABAergic interneurons）长期以来被认为通过与不同群体的锥体细胞建立非选择性连接来调控兴奋性网络，但近期研究表明存在细胞类型特异性的抑制性连接组（connectome）。中间神经元如何及何时在混合的兴奋性神经元群体中建立精确的连接模式仍未解开。这里，我们探究小鼠大脑皮层中调控细胞类型特异性抑制形成的分子机制。我们发现第5层皮层内神经元（L5 IT）和皮层外神经元（L5 ET）表达独特的转录程序，使其能够塑造小白蛋白阳性（PV+）和胆囊收缩素阳性（CCK+）中间神经元的连接。我们鉴定出钙粘蛋白超家族（cadherin superfamily）成员Cdh12和Cdh13是第5层锥体细胞群体细胞类型及输入特异性抑制模式的基础。多重单突触追踪（multiplex monosynaptic tracing）显示L5 IT和L5 ET的突触前抑制网络重叠极少，并提示不同的PV+篮状细胞群体支配不同的第5层锥体细胞类型。综上，我们的研究揭示了钙粘蛋白在塑造细胞类型特异性皮层中间神经元连接中的作用。