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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Risher, WC; Kim, N; Koh, S; Choi, J-E; Mitev, P; Spence, EF; Pilaz, L-J; Wang, D; Feng, G; Silver, DL; Soderling, SH; Yin, HH; Eroglu, C

Published Date

  • October 1, 2018

Published In

Volume / Issue

  • 217 / 10

Start / End Page

  • 3747 - 3765

PubMed ID

  • 30054448

Pubmed Central ID

  • PMC6168259

Electronic International Standard Serial Number (EISSN)

  • 1540-8140

Digital Object Identifier (DOI)

  • 10.1083/jcb.201802057


  • eng

Conference Location

  • United States