Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1
Journal of Cell Biology, 2018•rupress.org
Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which
function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug
target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in
both synaptic development and disease pathogenesis. However, the mechanism by which
this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of
the developing mammalian brain are unknown. In this study, we show that global or cell …
function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug
target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in
both synaptic development and disease pathogenesis. However, the mechanism by which
this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of
the developing mammalian brain are unknown. In this study, we show that global or cell …
Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit α2δ-1. α2δ-1 is a drug target for epilepsy and neuropathic pain; thus the TSP–α2δ-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for α2δ-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of α2δ-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic α2δ-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an α2δ-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP–α2δ-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology.
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