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Published December 10, 2008 | Supplemental Material + Published
Journal Article Open

SynGAP Regulates Steady-State and Activity-Dependent Phosphorylation of Cofilin

Abstract

SynGAP, a prominent Ras/Rap GTPase-activating protein in the postsynaptic density, regulates the timing of spine formation and trafficking of glutamate receptors in cultured neurons. However, the molecular mechanisms by which it does this are unknown. Here, we show that synGAP is a key regulator of spine morphology in adult mice. Heterozygous deletion of synGAP was sufficient to cause an excess of mushroom spines in adult brains, indicating that synGAP is involved in steady-state regulation of actin in mature spines. Both Ras- and Rac-GTP levels were elevated in forebrains from adult synGAP+/- mice. Rac is a well known regulator of actin polymerization and spine morphology. The steady-state level of phosphorylation of cofilin was also elevated in synGAP+/- mice. Cofilin, an F-actin severing protein that is inactivated by phosphorylation, is a downstream target of a pathway regulated by Rac. We show that transient regulation of cofilin by treatment with NMDA is also disrupted in synGAP mutant neurons. Treatment of wild-type neurons with 25 µM NMDA triggered transient dephosphorylation and activation of cofilin within 15 s. In contrast, neurons cultured from mice with a homozygous or heterozygous deletion of synGAP lacked the transient regulation by the NMDA receptor. Depression of EPSPs induced by a similar treatment of hippocampal slices with NMDA was disrupted in slices from synGAP+/- mice. Our data show that synGAP mediates a rate-limiting step in steady-state regulation of spine morphology and in transient NMDA-receptor-dependent regulation of the spine cytoskeleton.

Additional Information

Copyright © 2008 Society for Neuroscience. Received Sept. 30, 2008; accepted Oct. 27, 2008. This work was supported by National Institutes of Health (NIH) Grant NS17660 to M.B.K., by NIH Dorothy Kirschstein Fellowship F32NS47894 to H.J.C., and by donations to Caltech from Parna L. Joyce, Nancy A.E. Hicks, and the Gordon and Betty Moore Foundation. We thank Dr. Joshua Sanes (Harvard, Cambridge, MA) for GFP line-M transgenic mice, Dr. Brent Lindquist (Stony Brook University, Stony Brook, NY) for 3DMA spine analysis software, and Alan Rosenstein and Leslie Schenker for technical assistance.

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Published - CARjns08.pdf

Supplemental Material - CARjns08supp1.pdf

Supplemental Material - CARjns08supp2.pdf

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Created:
August 22, 2023
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October 17, 2023