Trans-Synaptic Interaction of GluRδ2 and Neurexin through Cbln1 Mediates Synapse Formation in the Cerebellum

Elucidation of molecular mechanisms that regulate synapse formation is required for the understanding of neural wiring, higher brain functions, and mental disorders. Despite the wealth of in vitro information, fundamental questions about how glutamatergic synapses are formed in the mammalian brain remain unanswered. Glutamate receptor (GluR) delta 2 is essential for cerebellar synapse formation in vivo. Here, we show that the N-terminal domain (NTD) of GluR delta 2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). The synaptogenic activity of GluR delta 2 is abolished in cerebellar primary cultures from Cbln1 knockout mice and is restored by recombinant Cbln1. Knockdown of NRXNs in cerebellar granule cells also hinders the synaptogenic activity of GluR delta 2. Both the NTD of GluR delta 2 and the extracellular domain of NRXN1 beta suppressed the synaptogenic activity of Cbln1 in cerebellar primary cultures and in vivo. These results suggest that GluR delta 2 mediates cerebellar synapse formation by interacting with presynaptic NRXNs through Cbln1.