Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1
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 dis...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Rockefeller University Press
2020
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| Online Access: | https://hdl.handle.net/1721.1/126047 |
| _version_ | 1826211945734209536 |
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| author | 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 |
| author2 | McGovern Institute for Brain Research at MIT |
| author_facet | McGovern Institute for Brain Research at MIT 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 |
| author_sort | Risher, W. Christopher |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:13:54Z |
| format | Article |
| id | mit-1721.1/126047 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:13:54Z |
| publishDate | 2020 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | mit-1721.1/1260472022-09-29T13:31:47Z Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 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 McGovern Institute for Brain Research at MIT 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. 2020-07-01T22:27:11Z 2020-07-01T22:27:11Z 2018-07 2018-05 2019-10-01T12:28:13Z Article http://purl.org/eprint/type/JournalArticle 0021-9525 1540-8140 https://hdl.handle.net/1721.1/126047 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 en http://dx.doi.org/10.1083/jcb.201802057 Journal of Cell Biology Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Rockefeller University Press Rockefeller University Press |
| spellingShingle | 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 Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title | Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title_full | Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title_fullStr | Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title_full_unstemmed | Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title_short | Thrombospondin receptor α2δ-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 |
| title_sort | thrombospondin receptor α2δ 1 promotes synaptogenesis and spinogenesis via postsynaptic rac1 |
| url | https://hdl.handle.net/1721.1/126047 |
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