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

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.; Soderling, Scott H.; Yin, Henry H.; Eroglu, Cagla; ... Show more Show less
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Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/
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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.
Date issued
2018-07
URI
https://hdl.handle.net/1721.1/126047
Department
McGovern Institute for Brain Research at MIT
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
ISSN
0021-9525
1540-8140

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