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

SummaryElucidation 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) δ2 is essential for cerebellar synapse formation in vivo. Here, we show that the N-terminal domain (NTD) of GluRδ2 interacts with presynaptic neurexins (NRXNs) through cerebellin 1 precursor protein (Cbln1). The synaptogenic activity of GluRδ2 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 GluRδ2. Both the NTD of GluRδ2 and the extracellular domain of NRXN1β suppressed the synaptogenic activity of Cbln1 in cerebellar primary cultures and in vivo. These results suggest that GluRδ2 mediates cerebellar synapse formation by interacting with presynaptic NRXNs through Cbln1.

Graphical AbstractFigure optionsDownload high-quality image (132 K)Download as PowerPoint slideHighlights
► Postsynaptic GluRδ2 interacts with presynaptic neurexins in the presence of Cbln1
► GluRδ2 selectively interacts with neurexin variants containing splice segment 4
► Synaptogenic activity of GluRδ2 requires both Cbln1 and neurexins
► The trans-synaptic GluRδ2-Cbln1-neurexin triad is essential for synapse formation