SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor

N. H. Komiyama, A. M. Watabe, H. J. Carlisle, K. Porter, P. Charlesworth, J. Monti, D. J.C. Strathdee, Colin M. O'Carroll, Stephen J. Martin, Richard G.M. Morris, Thomas J. O'Dell, Seth G.N. Grant

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    282 Citations (Scopus)

    Abstract

    At excitatory synapses, the postsynaptic scaffolding protein postsynaptic density 95 (PSD-95) couples NMDA receptors (NMDARs) to the Ras GTPase-activating protein SynGAP. The close association of SynGAP and NMDARs suggests that SynGAP may have an important role in NMDAR-dependent activation of Ras signaling pathways, such as the MAP kinase pathway, and in synaptic plasticity. To explore this issue, we examined long-term potentiation (LTP), p42 MAPK (ERK2) signaling, and spatial learning in mice with a heterozygous null mutation of the SynGAP gene (SynGAP-/+). In SynGAP-/+ mutant mice, the induction of LTP in the hippocampal CA1 region was strongly reduced in the absence of any detectable alteration in basal synaptic transmission and NMDAR-mediated synaptic currents. Although basal levels of activated ERK2 were elevated in hippocampal extracts from SynGAP-/+ mice, NMDAR stimulation still induced a robust increase in ERK activation in slices from SynGAP-/+ mice. Thus, although SynGAP may regulate the ERK pathway, its role in LTP most likely involves additional downstream targets. Consistent with this, the amount of potentiation induced by stimulation protocols that induce an ERK-independent form of LTP were also significantly reduced in slices from SynGAP-/+ mice. An elevation of basal phospho-ERK2 levels and LTP deficits were also observed in SynGAP-/+/H-Ras-/- double mutants, suggesting that SynGAP may normally regulate Ras isoforms other than H-Ras. A comparison of SynGAP and PSD-95 mutants suggests that PSD-95 couples NMDARs to multiple downstream signaling pathways with very different roles in LTP and learning.

    Original languageEnglish
    Pages (from-to)9721-9732
    Number of pages12
    JournalJournal of Neuroscience
    Volume22
    Issue number22
    Publication statusPublished - 15 Nov 2002

    Keywords

    • H-Ras
    • Hippocampus
    • Long-term potentiation
    • PSD-95
    • Spatial learning
    • SynGAP

    ASJC Scopus subject areas

    • General Neuroscience

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