Neuronal excitability coordinates the timing of input/output circuit assembly

How neurons coordinate the timing of migration, differentiation and synaptic integration with their specific inputs and outputs remains poorly understood. Here we show that granule cells, the brain's most numerous neuronal population, establish immature synaptic contacts on their output targets, the cerebellar Purkinje cells, well before completing their radial migration and becoming innervated by their mossy fiber inputs. This happens at a specific stage when granule cells reach the molecular layer and begin expressing presynaptic markers and a specific NMDA receptor subtype. Chemogenetic silencing of these migrating, differentiating granule cells shows that their excitability is required for output synapse maturation. Thus neuronal activity coordinates the timing of input and output synapse development. This mechanism might underlie GRIN2B-related pathologies that include autism spectrum disorders.