Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1.
JOURNAL OF CELL BIOLOGY(2018)
摘要
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.
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