Activity-dependent expression of Fezf2 regulates inhibitory synapse formation in pyramidal cells

The function of the cerebral cortex relies on the precise integration of diverse neuronal populations during development, which is regulated by dynamic fine-tuning mechanisms maintaining the balance between excitation and inhibition. For instance, the development of excitatory pyramidal cells is simultaneously and precisely counterbalanced by the formation of inhibitory synapses during the maturation of neuronal circuits. Although this process relies on neuronal activity, different types of pyramidal cells likely respond to changes in activity through the expression of cell-specific genes. However, the molecular programs underlying the activity-dependent recruitment of inhibition by distinct types of pyramidal cells in the neocortex are unknown. Here, we combined neuronal activity manipulation with ribosome-associated mRNA profiling of layer 5 (L5) extra-telencephalic (ET) cells to address this question in mice. We unveiled a novel function for the selector gene Fezf2 as an activity-dependent transcription factor controlling the parvalbumin inputs onto L5 ET neurons. One of the downstream effectors of FEZF2 shaping the formation of inhibitory synapses onto L5 ET pyramidal cells is the cell-surface molecule cadherin 22. Our study identifies activity-dependent factors regulating the cell type-specific assembly of inhibitory synapses onto pyramidal cells.