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Rapid Dispersion of SynGAP from Synaptic Spines Triggers AMPA Receptor Insertion and Spine Enlargement during LTP
Open accessAbstract
SynGAP is a Ras-GTPase activating protein highly enriched at excitatory synapses in the brain. Previous studies have shown that CaMKII and the RAS-ERK pathway are critical for several forms of synaptic plasticity including LTP. NMDA receptor-dependent calcium influx has been shown to regulate the RAS-ERK pathway and downstream events that result in AMPA receptor synaptic accumulation, spine enlargement, and synaptic strengthening during LTP. However, the cellular mechanisms whereby calcium influx and CaMKII control Ras activity remain elusive. Using live-imaging techniques, we have found that SynGAP is rapidly dispersed from spines upon LTP induction in hippocampal neurons, and this dispersion depends on phosphorylation of SynGAP by CaMKII. Moreover, the degree of acute dispersion predicts the maintenance of spine enlargement. Thus, the synaptic dispersion of SynGAP by CaMKII phosphorylation during LTP represents a key signaling component that transduces CaMKII activity to small G protein-mediated spine enlargement, AMPA receptor synaptic incorporation, and synaptic potentiation.
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“To test this, we induced long-term potentiation via APV withdrawal and glycine stimulation19 which resulted in an increase in PSD-95 localization density within NCs, the percentage of PSD-95 NCs enriched with RIM1/2, and the enrichment index of PSD-95 NCs (Fig. 4a–c, Extended Data Fig. 10m).”
From A trans-synaptic nanocolumn aligns neurotransmitter release to receptors (2016) · cites this paper as [19]
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“we induced long-term potentiation via APV withdrawal and glycine stimulation19”
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“Several mechanisms should be considered, including indirect effects on synaptic features such as activity, which regulates the targeting of SYNGAP1 through its phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CAMK2).54”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [54]
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“Imaging studies have reported that this phosphorylation triggers movement of SynGAP out of the PSD (304, 305)”
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“Furthermore, knockdown of SynGAP results in the accumulation of synaptic AMPARs, which occludes chemLTP (304).”
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“and this dispersal is required for chemLTP (304).”
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“CaMKII phosphorylates SynGAP and decreases its binding to PSD-95 (302, 304).”
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“Synaptic GTPase activating protein 1 (SynGAP1) is a Ras-GTPase activating protein localized in the PSD in glutamatergic neurons [66, 197] and involved in dendritic spine maturation, glutamate receptor trafficking and synaptic function [11].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [11]
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Metadata
- Authors
- Araki, Y., Zeng, M., Zhang, M., & Huganir, R. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Huganir, Richard L.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 85
- Issue
- 1
- Pages
- 173-189
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC4428669
- OpenAlex
- W1993505652
- Cited by
- 271
- References
- 57
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 36 · 2023: 22 · 2022: 23 · 2021: 15 · 2020: 31 · 2019: 20 · 2018: 29 · 2017: 19 · 2016: 18 · 2015: 9
- FWCI
- 11.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (MH64856, R01MH064856)
- National Institute of Neurological Disorders and Stroke (R01NS036715, NS036715, R37NS036715)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- SynGAP, CaMKII, long-term potentiation, Ras/ERK pathway, synaptic plasticity, hippocampal neurons, small GTPases, synaptic potentiation
- MeSH terms
- Animals, Calcium, Hippocampus, Neuronal Plasticity, Neurons, Phosphorylation, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Long-Term Potentiation, Receptors, AMPA, ras Proteins, GTPase-Activating Proteins, MAP Kinase Signaling System, Long-Term Synaptic Depression, Dendritic Spines, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 2
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