SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons
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Silent synapses, or excitatory synapses that lack functional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), are thought to be critical for regulation of neuronal circuits and synaptic plasticity. Here, we report that SynGAP, an excitatory synapse-specific RasGAP, regulates AMPAR trafficking, silent synapse number, and excitatory synaptic transmission in hippocampal and cortical cultured neurons. Overexpression of SynGAP in neurons results in a remarkable depression of AMPAR-mediated miniature excitatory postsynaptic currents, a significant reduction in synaptic AMPAR surface expression, and a decrease in the insertion of AMPARs into the plasma membrane. This change is specific for AMPARs because no change is observed in synaptic NMDA receptor expression or total synapse density. In contrast to these results, synaptic transmission is increased in neurons from SynGAP knockout mice as well as in neuronal cultures treated with SynGAP small interfering RNA. In addition, activation of the extracellular signal-regulated kinase, ERK, is significantly decreased in SynGAP-overexpressing neurons, whereas P38 mitogen-activated protein kinase (MAPK) signaling is potentiated. Furthermore, ERK activation is up-regulated in neurons from SynGAP knockout mice, whereas P38 MAPK function is depressed. Taken together, these data suggest that SynGAP plays a critical role in the regulation of neuronal MAPK signaling, AMPAR membrane trafficking, and excitatory synaptic transmission.
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SynGAP expression is inversely correlated with synaptic AMPA receptor levels but not with NMDA receptor levels.
“Studies using in vitro systems and KO mice have shown that SynGAP expression is inversely correlated to the levels of AMPA receptors, but not NMDA receptors, at the synapse [306].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [306]
Disrupting SynGAP expression in dissociated hippocampal neurons can enhance or suppress dendritic spine function.
“In addition, disrupting SynGAP expression in dissociated hippocampal neurons can enhance dendritic spine function (Kim et al., 2005; Rumbaugh et al., 2006) or suppress it (Krapivinsky et al., 2004).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Rumbaugh et al., 2006
Depending on the SynGAP variant expressed, SynGAP can either stimulate or suppress dendritic spine synapse function.
“depending on the variant expressed, SynGAP can either stimulate (Rumbaugh et al., 2006) or suppress dendritic spine synapse function (McMahon et al., 2012).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Rumbaugh et al., 2006
The LoxP-STOP cassette would be expected to cause truncation of full-length protein, which is known to inactivate SynGAP.
“This cassette would be expected to cause a truncation of full-length protein, which is known to inactivate SynGAP (Rumbaugh et al., 2006).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Rumbaugh et al., 2006
SynGAP shapes developmental synaptic function through its synaptic GAP activity, suppressing biochemical signaling cascades in dendritic spines that promote synapse growth and AMPA receptor insertion.
“Mechanistically, SynGAP shapes developmental synaptic function through its synaptic GAP activity, where it suppresses many biochemical signaling cascades within dendritic spines that promote growth of synapses and insertion of AMPARs (Kim et al., 2005; Krapivinsky et al., 2004; Rumbaugh et al., 2006).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as Rumbaugh et al., 2006
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 Rumbaugh et al., 2006
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 Rumbaugh et al., 2006
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- Authors
- Rumbaugh, G., Adams, J. P., Kim, J. H., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- Department of Developmental Biology, The Rockefeller University, New York, NY 10021
- Corresponding author
- Huganir, Richard L.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2006-03-14
- Volume
- 103
- Issue
- 12
- Pages
- 4344-4351
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1450173
- OpenAlex
- W2046170065
- Cited by
- 260
- References
- 40
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 21 · 2023: 13 · 2022: 10 · 2021: 7 · 2020: 23 · 2019: 9 · 2018: 14 · 2017: 12 · 2016: 12 · 2015: 8 · 2014: 11 · 2013: 10 · 2012: 12
- FWCI
- 5.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH064856)
- National Institute of Neurological Disorders and Stroke (F32NS043071)
- 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, silent synapses, AMPA receptor trafficking, excitatory synaptic transmission, Ras GTPase-activating protein, ERK signaling, p38 MAPK, synaptic plasticity, miniature excitatory postsynaptic currents, hippocampal neurons, cortical neurons
- MeSH terms
- Animals, Cells, Cultured, Mutation, Synaptic Transmission, Neurons, Synapses, Receptors, AMPA, Mice, Knockout, ras GTPase-Activating Proteins, Mitogen-Activated Protein Kinases, Protein Transport, Extracellular Signal-Regulated MAP Kinases, p38 Mitogen-Activated Protein Kinases, Mice, Rats
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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