SynGAP Regulates ERK/MAPK Signaling, Synaptic Plasticity, and Learning in the Complex with Postsynaptic Density 95 and NMDA Receptor

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.

Age-related accumulation of Reelin in amyloid-like deposits

“…These findings extend previous observations in mutant SynGAP mice showing increased neuronal apoptosis during late embryonic and early postnatal development . These mice also have reduced LTP and perform poorly in spatial memory tasks (Kim et al, 2003;Komiyama et al, 2002), indicating that neurodevelopmental abnormalities affecting Reelin expression impair cognitive performance in adulthood.…”

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010]. SYNGAP1 [603384] has been coded in Online Mendelian Inheritance in Man (OMIM ® ) as causing mental retardation, autosomal dominant 5 [612621].…”

Mutationsde novodeSYNGAP1associées à la déficience intellectuelle non syndromique

“…Le rôle de SYNGAP pourrait être de restreindre dans le temps l'activation de RAS-ERK au cours de certaines phases de la plasticité synaptique. Les souris homozygotes pour un allèle nul de Syngap1 meurent à la naissance tandis que les souris hétérozygotes survivent mais ont des perturbations de la mémoire et des apprentissages [3,6].…”

“…Processus cognitifs et plasticité synaptique : cibles de la déficience intellectuelle non syndromique Les processus cognitifs, comme la mémoire et les apprentissages, AMPAR dans la membrane post-synaptique en inhibant la voie RAS-ERK (Figure 1) [3][4][5]. Le rôle de SYNGAP pourrait être de restreindre dans le temps l'activation de RAS-ERK au cours de certaines phases de la plasticité synaptique.…”

“…Le rôle de SYNGAP pourrait être de restreindre dans le temps l'activation de RAS-ERK au cours de certaines phases de la plasticité synaptique. Les souris homozygotes pour un allèle nul de Syngap1 meurent à la naissance tandis que les souris hétérozygotes survivent mais ont des perturbations de la mémoire et des apprentissages [3,6].Haplo-insuffisance de SYNGAP1 à l'origine de déficience intellectuelle L'hypothèse de notre groupe est que des mutations ponctuelles de novo touchant des gènes essentiels pour la plasticité synaptique pourraient expliquer une fraction des cas de DINS. Pour l'explorer, nous avons entrepris de séquencer un grand nombre de gènes intervenant dans le processus de plasticité synaptique dans une cohorte d'enfants atteints de DINS.…”