Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1
Name
JCB_201802057.pdf
Description
Published version
Size
2.79 MB
Format
Adobe PDF
Checksum (MD5)
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Author(s)
Risher, W. Christopher
Kim, Namsoo
Koh, Sehwon
Choi, Ji-Eun
Mitev, Petar
Spence, Erin F.
Pilaz, Louis-Jan
Wang, Dongqing
Feng, Guoping
Silver, Debra L.
Date Issued
July 2018
Journal
Journal of Cell Biology
Publisher
Rockefeller University Press
Citation
Risher, W. Christopher et al. "Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1." Journal of Cell Biology 217, 10 (July 2018): 3747–3765 © 2018 The Authors
Version
Final published version
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.
MIT Department
McGovern Institute for Brain Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1083/jcb.201802057
