Phospholipase C-[beta]1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration

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dc.contributor.authorMcOmish, CEko
dc.contributor.authorBurrows, Eko
dc.contributor.authorHoward, Mko
dc.contributor.authorScarr, Eko
dc.contributor.authorKim, Daesooko
dc.contributor.authorShin, Hee-Supko
dc.contributor.authorDean, Bko
dc.contributor.authorBuuse, M van denko
dc.contributor.authorHannan, AJko
dc.date.accessioned2011-03-24T09:05:29Z-
dc.date.available2011-03-24T09:05:29Z-
dc.date.created2012-02-06-
dc.date.created2012-02-06-
dc.date.issued2008-07-
dc.identifier.citationMOLECULAR PSYCHIATRY, v.13, no.7, pp.661 - 672-
dc.identifier.issn1359-4184-
dc.identifier.urihttp://hdl.handle.net/10203/22997-
dc.description.abstractPhospholipase C-beta 1 (PLC-beta 1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-beta 1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-beta 1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-beta 1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene-environment interactions.-
dc.description.sponsorshipWe thank L Gray, J Nithianantharajah and C Hannan for comments on manuscript drafts. This work was supported by NHMRC project grants and an RD Wright award (AJH). AJH currently holds a Pfizer Australia Senior Research Fellowship. BD is an NHMRC Senior Research Fellow. ES is the Ronald Griffith Schizophrenia Research Fellow. Funding was also provided by Trust Company Australia (CEM).en
dc.languageEnglish-
dc.language.isoen_USen
dc.publisherNature Publishing Group-
dc.subjectMUSCARINIC ACETYLCHOLINE-RECEPTOR-
dc.subjectBRAIN CORTICAL MEMBRANES-
dc.subjectSUPERIOR TEMPORAL CORTEX-
dc.subjectWORKING-MEMORY DEFICITS-
dc.subjectACOUSTIC STARTLE REFLEX-
dc.subjectPREPULSE INHIBITION-
dc.subjectNEUROTRANSMITTER RECEPTORS-
dc.subjectGLUTAMATE RECEPTORS-
dc.subjectANTIPSYCHOTIC-DRUGS-
dc.subjectPREFRONTAL CORTEX-
dc.titlePhospholipase C-[beta]1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration-
dc.typeArticle-
dc.identifier.wosid000256832700005-
dc.identifier.scopusid2-s2.0-45549107762-
dc.type.rimsART-
dc.citation.volume13-
dc.citation.issue7-
dc.citation.beginningpage661-
dc.citation.endingpage672-
dc.citation.publicationnameMOLECULAR PSYCHIATRY-
dc.identifier.doi10.1038/sj.mp.4002046-
dc.embargo.liftdate9999-12-31-
dc.embargo.terms9999-12-31-
dc.contributor.localauthorKim, Daesoo-
dc.contributor.nonIdAuthorMcOmish, CE-
dc.contributor.nonIdAuthorBurrows, E-
dc.contributor.nonIdAuthorHoward, M-
dc.contributor.nonIdAuthorScarr, E-
dc.contributor.nonIdAuthorShin, Hee-Sup-
dc.contributor.nonIdAuthorDean, B-
dc.contributor.nonIdAuthorBuuse, M van den-
dc.contributor.nonIdAuthorHannan, AJ-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorschizophrenia-
dc.subject.keywordAuthormuscarinic receptors-
dc.subject.keywordAuthorenvironmental enrichment-
dc.subject.keywordAuthorantipsychotics-
dc.subject.keywordAuthorclozapine-
dc.subject.keywordAuthorhaloperidol-
dc.subject.keywordPlusMUSCARINIC ACETYLCHOLINE-RECEPTOR-
dc.subject.keywordPlusBRAIN CORTICAL MEMBRANES-
dc.subject.keywordPlusSUPERIOR TEMPORAL CORTEX-
dc.subject.keywordPlusWORKING-MEMORY DEFICITS-
dc.subject.keywordPlusACOUSTIC STARTLE REFLEX-
dc.subject.keywordPlusPREPULSE INHIBITION-
dc.subject.keywordPlusNEUROTRANSMITTER RECEPTORS-
dc.subject.keywordPlusGLUTAMATE RECEPTORS-
dc.subject.keywordPlusANTIPSYCHOTIC-DRUGS-
dc.subject.keywordPlusPREFRONTAL CORTEX-
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