title: 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.
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, The University of Alabama at Birmingham, Birmingham, AL 35294 , USA.
authors.forename: Xiaochuan
authors.initials: X
authors.lastname: Guo
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hamilton
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Reish
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000627:therapeutic use; D001522:Behavior, Animal; D001526:Behavioral Symptoms / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics*; D003024:Clozapine / Q000627:therapeutic use; D018592:Cross-Over Studies; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007266:Inhibition, Psychological; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D008570:Memory, Short-Term / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009483:Neuropsychological Tests; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D012559:Schizophrenia / Q000150:complications* / Q000188:drug therapy / Q000235:genetics*; D012919:Social Behavior; D013239:Stereotyped Behavior / Q000502:physiology; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins; D016291:Dizocilpine Maleate; D003024:Clozapine