SynGAP Regulates Steady-State and Activity-Dependent Phosphorylation of Cofilin
Open accessAbstract
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 μ m 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.
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In adult mouse hippocampal CA1, mushroom spine density is increased in Syngap1+/− mice compared with wild-type, while thin and stubby spine densities are not increased.
“In the hippocampal CA1 of adult mice, the density of mushroom spines, but not those of thin or stubby spines, is increased in Syngap1+/− mice compared to WT mice [51]”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [51]
These results are consistent with signaling deficits previously reported in adult SynGAP mice.
“These results are consistent with signaling deficits previously reported in adult SynGAP mice (Carlisle et al., 2008; Komiyama et al., 2002).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Carlisle et al., 2008
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- Authors
- Carlisle, H. J., Manzerra, P., Marcora, E., & Kennedy, M. B.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Kennedy, Mary B.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-12-10
- Volume
- 28
- Issue
- 50
- Pages
- 13673-13683
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2615239
- OpenAlex
- W2095421300
- Cited by
- 128
- References
- 57
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 9 · 2019: 4 · 2018: 8 · 2017: 5 · 2016: 9 · 2015: 7 · 2014: 10 · 2013: 8 · 2012: 10
- FWCI
- 4.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Gordon and Betty Moore Foundation
- California Institute of Technology
- National Institutes of Health (1f32ns047894-01)
- National Institute of Neurological Disorders and Stroke (R01NS017660, NS-17660, F32NS47894, F32 NS047894)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- SynGAP, cofilin phosphorylation, dendritic spine morphology, mushroom spines, actin cytoskeleton, Rac GTPase, Ras GTPase, NMDA receptor, activity-dependent regulation, postsynaptic density, glutamate receptor trafficking, synaptic plasticity, hippocampus
- MeSH terms
- Animals, Brain, Cytoskeleton, Electrophoresis, Polyacrylamide Gel, Organ Culture Techniques, Phosphorylation, Blotting, Western, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate, Mice, Knockout, Patch-Clamp Techniques, Microscopy, Confocal, ras Proteins, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, ras GTPase-Activating Proteins, rac GTP-Binding Proteins, Long-Term Synaptic Depression, Dendritic Spines, Actin Depolymerizing Factors, Mice
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