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

• DOI: 10.1083/jcb.201802057
• Publication Date: 2018-07-27T14:45:17Z
• Authors: W. Christopher Ri...; Namsoo Kim; Sehwon Koh; Ji-Eun Choi; Petar Mitev; Erin F. Spence; Louis-Jan Pilaz; Dongqing Wang; Guoping Feng; Debra L. Silver; Scott H. Soderling; Henry H. Yin; Cagla Eroglu
• Keywords: Cerebral Cortex; rac1 GTP-Binding Protein; 0301 basic medicine; Neuropeptides; Mice, Transgenic; Embryo, Mammalian; Spine; 03 medical and health sciences; Astrocytes; Synapses; Animals; Calcium Channels; Autistic Disorder; Research Articles

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.