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J Cell Biol DOI:10.1083/jcb.201802057

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

Publication TypeJournal Article
Year of Publication2018
AuthorsW Risher, C, 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
JournalJ Cell Biol
Volume217
Issue10
Pages3747-3765
Date Published2018 Oct 01
ISSN1540-8140
Abstract

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.

DOI10.1083/jcb.201802057
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30054448?dopt=Abstract

Alternate JournalJ. Cell Biol.
PubMed ID30054448
PubMed Central IDPMC6168259
Grant ListR01 NS096352 / NS / NINDS NIH HHS / United States
R01 NS102237 / NS / NINDS NIH HHS / United States
F32 NS083283 / NS / NINDS NIH HHS / United States
R01 NS094754 / NS / NINDS NIH HHS / United States
R01 DA031833 / DA / NIDA NIH HHS / United States