Reduced Expression of the NMDA Receptor-Interacting Protein SynGAP Causes Behavioral Abnormalities that Model Symptoms of Schizophrenia

Abstract

Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited nonhabituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data in dicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.

Reduced expression of SynGAP, a neuronal GTPase-activating protein, enhances capsaicin-induced peripheral sensitization

“…With the use of a separately generated SynGAP ϩ/Ϫ mouse, Muhia et al (2010) also demonstrated no difference in the withdrawal latency to thermal stimulation with altered SynGAP expression. Although Syn-GAP ϩ/Ϫ mice, similar to the strain we used, exhibited an increase in spontaneous, seemly purposeless, open-field activity and an increased startle response, there was no evidence of gross sensory or motor dysfunction reported in these animals (Guo et al 2009). …”

“…This GAP plays an important role in models of synaptic plasticity (Kim et al 2003;Komiyama et al 2002;Rumbaugh et al 2006), apoptosis (Knuesel et al 2005), and schizophrenia (Guo et al 2009). SynGAP is associated with proteins in the postsynaptic density, including postsynaptic density-95 kDa and the N-methyl-D-aspartate (NMDA) receptor (Chen et al 1998;Kim et al 1998), and plays a crucial role in early development, since SynGAP knockout mice die within 1 wk of birth (Kim et al 1998).…”

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].…”

“…En effet, le complexe Elongator, et plus particulièrement sa sous-unité Elp3, possède une activité histone acétyl-transférase envers l'histone H3, rendant ainsi possible la progression de l'ARN polymérase II au niveau de la région transcrite de certains gènes [4,5]. Des études récentes ont démontré qu'Elongator remplit aussi des fonctions dans le cytoplasme, comme la régulation de l'exocytose et la modification de certains ARN de transfert [6,7].…”

“…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.…”