SynGAP isoforms exert opposing effects on synaptic strength

McMahon, A.C.; Barnett, M.W.; O'Leary, T.S.; Stoney, P.N.; Collins, M.O.; Papadia, S.; Choudhary, J.S.; Komiyama, N.H.; Grant, S.G.N.; Hardingham, G.E.; Wyllie, D.J.A.; Kind, P.C.

doi:10.1038/ncomms1900

Cited by 91Neuroscience and Neuropharmacology ResearchRNA Research and SplicingGenetics and Neurodevelopmental Disorders

SynGAP isoforms exert opposing effects on synaptic strength

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McMahon, A.C., Barnett, M.W., O'Leary, T.S., Stoney, P.N., Collins, M.O., Papadia, S., Choudhary, J.S., Komiyama, N.H. +4 more·2012·Nature Communications

DOI 10.1038/ncomms1900PMC PMC3621422

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Abstract

Alternative promoter usage and alternative splicing enable diversification of the transcriptome. Here we demonstrate that the function of Synaptic GTPase-Activating Protein (SynGAP), a key synaptic protein, is determined by the combination of its amino-terminal sequence with its carboxy-terminal sequence. 5′ rapid amplification of cDNA ends and primer extension show that different N-terminal protein sequences arise through alternative promoter usage that are regulated by synaptic activity and postnatal age. Heterogeneity in C-terminal protein sequence arises through alternative splicing. Overexpression of SynGAP α1 versus α2 C-termini-containing proteins in hippocampal neurons has opposing effects on synaptic strength, decreasing and increasing miniature excitatory synaptic currents amplitude/frequency, respectively. The magnitude of this C-terminal-dependent effect is modulated by the N-terminal peptide sequence. This is the first demonstration that activity-dependent alternative promoter usage can change the function of a synaptic protein at excitatory synapses. Furthermore, the direction and degree of synaptic modulation exerted by different protein isoforms from a single gene locus is dependent on the combination of differential promoter usage and alternative splicing. Synaptic GTPase-activating protein, SynGAP, is a postsynaptic signalling protein that can regulate synaptic function. McMahonet al. express different SynGAP isoforms in neurons and find that the effect on synaptic strength depends on alternative promoter usage and alternative splicing of the C-terminus.

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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 McMahon et al., 2012
A recent report demonstrated that SynGAP can enhance or inhibit dendritic spine synapse function depending on the isoform expressed.
“Adding to the confusion, a recent report has demonstrated that SynGAP can enhance or inhibit dendritic spine synapse function depending on the particular isoform expressed (McMahon et al., 2012).”
From Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses (2012) · cites this paper as McMahon et al., 2012

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Examination of multiple SynGAP isoforms in mammalian central neurons
McMahon, A. C. (2011) · ERA
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SynGAP splice variants display heterogeneous spatio‐temporal expression and subcellular distribution in the developing mammalian brain
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Authors: McMahon, A. C., Barnett, M. W., O'Leary, T. S., Stoney, P. N., Collins, M. O., Papadia, S., Choudhary, J. S., Komiyama, N. H., Grant, S. G. N., Hardingham, G. E., Wyllie, D. J. A., & Kind, P. C.
Affiliations: University of Edinburgh (GB)
Wellcome Sanger Institute (GB)
Corresponding author: McMahon, A.C.
Wyllie, D.J.A.
Kind, P.C.
ORCID: McMahon, A.C.
Barnett, M.W.
Stoney, P.N.
Collins, M.O.
Papadia, S.
Choudhary, J.S.
Komiyama, N.H.
Grant, S.G.N.
Hardingham, G.E.
Wyllie, D.J.A.
Kind, P.C.
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2012-06-12
Volume: 3
Issue: 1
Pages: 900-900
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/ncomms1900
PMC: PMC3621422
OpenAlex: W1995780026
Cited by: 91
References: 28
Citations by year: 2026: 5 · 2025: 13 · 2024: 11 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 12 · 2019: 4 · 2018: 4 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 2 · 2013: 4 · 2012: 1
FWCI: 1.71
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/3.0/ (tdm)
creativecommons.org/licenses/by-nc-sa/3.0/ (vor)
Locations: Nature Communications (publishedVersion, cc-by-nc-sa)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion, cc-by-nc-sa)
PubMed (publishedVersion)
White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
Aberdeen University Research Archive (Aberdeen University) (submittedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Cambridge University Engineering Department Publications Database (submittedVersion)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-sa)
Apollo (University of Cambridge) (submittedVersion, cc-by-nc-sa)
Apollo
Funders: Wellcome Trust (241995)
European Commission (242167)
Medical Research Council
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: SynGAP, protein isoforms, alternative promoters, alternative splicing, synaptic efficacy, excitatory synapses, miniature excitatory postsynaptic currents, N-terminal sequence, C-terminal sequence, hippocampal neurons, activity-dependent gene regulation
MeSH terms: Amino Acid Sequence, Animals, Electrophysiology, Hippocampus, Mice, Inbred C57BL, Molecular Sequence Data, Neurons, Mass Spectrometry, Synapses, Protein Isoforms, ras GTPase-Activating Proteins, Mice

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