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

Publication ,  Journal Article
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 in: J Cell Biol
October 1, 2018

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.

Duke Scholars

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Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

October 1, 2018

Volume

217

Issue

10

Start / End Page

3747 / 3765

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Synapses
  • Spine
  • Neuropeptides
  • Mice, Transgenic
  • Embryo, Mammalian
  • Developmental Biology
  • Cerebral Cortex
  • Calcium Channels
  • Autistic Disorder
 

Citation

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Risher, W. C., Kim, N., Koh, S., Choi, J.-E., Mitev, P., Spence, E. F., … Eroglu, C. (2018). Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol, 217(10), 3747–3765. https://doi.org/10.1083/jcb.201802057
Risher, W Christopher, Namsoo Kim, Sehwon Koh, Ji-Eun Choi, Petar Mitev, Erin F. Spence, Louis-Jan Pilaz, et al. “Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1.J Cell Biol 217, no. 10 (October 1, 2018): 3747–65. https://doi.org/10.1083/jcb.201802057.
Risher WC, Kim N, Koh S, Choi J-E, Mitev P, Spence EF, et al. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol. 2018 Oct 1;217(10):3747–65.
Risher, W. Christopher, et al. “Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1.J Cell Biol, vol. 217, no. 10, Oct. 2018, pp. 3747–65. Pubmed, doi:10.1083/jcb.201802057.
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. Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1. J Cell Biol. 2018 Oct 1;217(10):3747–3765.

Published In

J Cell Biol

DOI

EISSN

1540-8140

Publication Date

October 1, 2018

Volume

217

Issue

10

Start / End Page

3747 / 3765

Location

United States

Related Subject Headings

  • rac1 GTP-Binding Protein
  • Synapses
  • Spine
  • Neuropeptides
  • Mice, Transgenic
  • Embryo, Mammalian
  • Developmental Biology
  • Cerebral Cortex
  • Calcium Channels
  • Autistic Disorder