Document Type
Article
Publication Date
10-1-2018
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.
Recommended Citation
Risher WC, Kim N, Koh S, Choi JE, Mitev P, Spence EF, Pilaz LJ, Wang D, Feng G, Silver DL, Soderling SH. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. Journal of Cell Biology. 2018 Oct 1;217(10):3747-65.
Comments
The copy of record is available from the publisher at https://doi.org/10.1083/jcb.201802057. Copyright © 2018 Risher et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/)