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 Cdh12 and Cdh13, 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.