SynGAP regulates spine formation
Open accessAbstract
SynGAP is a brain-specific ras GTPase-activating protein that is an abundant component of the signaling complex associated with the NMDA-type glutamate receptor. We generated mutant mice lacking synGAP to study its physiological role. Homozygous mutant mice die in the first few days after birth; however, neurons from mutant embryos can be maintained in culture. Here, we report that spine and synapse formation are accelerated in cultured mutant neurons, and the spines of mature mutant neurons are significantly larger than those of wild type. Clusters of PSD-95 and subunits of AMPA-type and NMDA-type glutamate receptors accumulate in spines of mutant neurons by day 10 in vitro , whereas in wild-type neurons they are still mostly located in dendritic shafts. The frequency and amplitude of miniature EPSCs are larger in mutant neurons at day 10 in vitro , confirming that they have more functional synapses. At day 21 in vitro , the spines of mutant neurons remain significantly larger than those of wild type. The mutant phenotype at day 10 in vitro can be rescued by introduction of recombinant wild-type synGAP on day 9. In contrast, introduction of mutant synGAP with a mutated GAP domain or lacking the terminal domain that binds to PSD-95 does not rescue the mutant phenotype, indicating that both domains play a role in control of spine formation. Thus, the GAP activity of synGAP and its association with PSD-95 are important for normal regulation of spine and synapse formation in hippocampal neurons.
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These findings are consistent with SynGAP acting as an essential repressive factor that contributes to the developmental trajectory of glutamatergic synapse maturation.
“These findings are consistent with the role of SynGAP as an essential repressive factor that contributes to the developmental trajectory of glutamatergic synapse maturation (Kim et al., 2003; Rumbaugh et al., 2006; Vazquez et al., 2004).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Vazquez et al., 2004
The role of SynGAP in regulating dendritic spine synapse function has been controversial, with some studies reporting repression and others stimulation.
“However, the role that SynGAP plays in neurons to regulate dendritic spine synapse function has been controversial because some studies report that SynGAP is a repressor of these synapses (Kim et al., 2005; Rumbaugh et al., 2006; Vazquez et al., 2004), while others report that it stimulates them (Krapivinsky et al., 2004; McMahon et al., 2012).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Vazquez et al., 2004
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- Authors
- Vazquez, L. E., Chen, H.-J., Sokolova, I., Knuesel, I., & Kennedy, M. B.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Kennedy, Mary B.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2004-10-06
- Volume
- 24
- Issue
- 40
- Pages
- 8862-8872
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6729942
- OpenAlex
- W2165462647
- Cited by
- 203
- References
- 30
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 9 · 2023: 6 · 2022: 5 · 2021: 11 · 2020: 17 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 8 · 2015: 3 · 2014: 6 · 2013: 9 · 2012: 10
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (5p50mh049176-10)
- National Institute of Mental Health (MH49176, T32MH020069)
- National Institute of Neurological Disorders and Stroke (R01NS028710, R01NS017660, NS-17660, NS28710)
- 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, dendritic spine formation, synaptogenesis, NMDA receptor signaling, PSD-95, AMPA receptors, miniature EPSCs, hippocampal neurons, GTPase-activating protein, synapse maturation
- MeSH terms
- Disks Large Homolog 4 Protein, Animals, Cells, Cultured, Hippocampus, Membrane Proteins, Nerve Tissue Proteins, Neurons, Phenotype, Protein Structure, Tertiary, Mice, Knockout, Excitatory Postsynaptic Potentials, ras GTPase-Activating Proteins, Intracellular Signaling Peptides and Proteins, Dendritic Spines, Mice, Guanylate Kinases
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