SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity
Open accessAbstract
SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1 -knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1 -related neurodevelopmental disorders.
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The GAP activity of SYNGAP1 is dispensable for synaptic plasticity and learning in adult mice.
“The GAP activity of SYNGAP1 was recently shown to be dispensable for synaptic plasticity and learning in adult mice.57,58”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [57]
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References 45 · Cited by 92
- Authors
- Araki, Y., Rajkovich, K. E., Gerber, E. E., Gamache, T. R., Johnson, R. C., Tran, T. H. N., Liu, B., Zhu, Q., Hong, I., Kirkwood, A., & Huganir, R.
- Affiliations
- Johns Hopkins University (US)
- Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
- Corresponding author
- Araki, Yoichi
- Rajkovich, Kacey E.
- Gerber, Elizabeth E.
- Gamache, Timothy R.
- Huganir, Richard
- ORCID
- Venue
- Science
- Published
- 2024-03
- Volume
- 383
- Issue
- 6686
- Pages
- eadk1291-eadk1291
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC11188940
- OpenAlex
- W4392282691
- Cited by
- 92
- References
- 45
- Citations by year
- 2026: 30 · 2025: 37 · 2024: 25
- FWCI
- 16.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (T32MH015330, R01MH112151)
- National Institute of Neurological Disorders and Stroke (R01NS036715, T32NS091018, R37NS036715)
- 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, SYNGAP1, synaptic plasticity, synaptic efficacy, AMPA receptors, TARP, synaptic scaffolding proteins, molecular condensates, GTPase-activating protein, intellectual disability, autism spectrum disorder, epilepsy, learning and memory, neurodevelopmental disorders, non-catalytic function
- MeSH terms
- Animals, Autistic Disorder, Catalysis, Cognition, Humans, Learning, Neuronal Plasticity, Mice, Knockout, GTPase-Activating Proteins, ras GTPase-Activating Proteins, Mice
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