| First Author | Risher WC | Year | 2018 |
| Journal | J Cell Biol | Volume | 217 |
| Issue | 10 | Pages | 3747-3765 |
| PubMed ID | 30054448 | Mgi Jnum | J:266010 |
| Mgi Id | MGI:6201845 | Doi | 10.1083/jcb.201802057 |
| Citation | Risher WC, et al. (2018) Thrombospondin receptor alpha2delta-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol 217(10):3747-3765 |
| abstractText | Astrocytes control excitatory synaptogenesis by secreting thrombospondins (TSPs), which function via their neuronal receptor, the calcium channel subunit alpha2delta-1. alpha2delta-1 is a drug target for epilepsy and neuropathic pain; thus the TSP-alpha2delta-1 interaction is implicated in both synaptic development and disease pathogenesis. However, the mechanism by which this interaction promotes synaptogenesis and the requirement for alpha2delta-1 for connectivity of the developing mammalian brain are unknown. In this study, we show that global or cell-specific loss of alpha2delta-1 yields profound deficits in excitatory synapse numbers, ultrastructure, and activity and severely stunts spinogenesis in the mouse cortex. Postsynaptic but not presynaptic alpha2delta-1 is required and sufficient for TSP-induced synaptogenesis in vitro and spine formation in vivo, but an alpha2delta-1 mutant linked to autism cannot rescue these synaptogenesis defects. Finally, we reveal that TSP-alpha2delta-1 interactions control synaptogenesis postsynaptically via Rac1, suggesting potential molecular mechanisms that underlie both synaptic development and pathology. |
