Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1

Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit alpha 2 delta-1. alpha 2 delta-1 is a drug target for epilepsy and neuropathic pain; thus the TSP-alpha 2 delta-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for alpha 2 delta-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of alpha 2 delta-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic alpha 2 delta-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an alpha 2 delta-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP-alpha 2 delta-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology.