TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain

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dc.contributor.authorJang, Yongwooko
dc.contributor.authorLee, Sung Hoonko
dc.contributor.authorLee, Byeongjunko
dc.contributor.authorJung, Seungmoonko
dc.contributor.authorKhalid, Arshiko
dc.contributor.authorUchida, Kunitoshiko
dc.contributor.authorTominaga, Makotoko
dc.contributor.authorJeon, Daejongko
dc.contributor.authorOh, Uhtaekko
dc.date.accessioned2016-04-20T06:30:10Z-
dc.date.available2016-04-20T06:30:10Z-
dc.date.created2015-11-02-
dc.date.created2015-11-02-
dc.date.issued2015-08-
dc.identifier.citationJOURNAL OF NEUROSCIENCE, v.35, no.34, pp.11811 - 11823-
dc.identifier.issn0270-6474-
dc.identifier.urihttp://hdl.handle.net/10203/205384-
dc.description.abstractBipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca2+-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the Trpm2(-/-) mice. The brains of Trpm2(-/-) mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca2+-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of Trpm2 causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between Trpm2 mutation and BD.-
dc.languageEnglish-
dc.publisherSOC NEUROSCIENCE-
dc.subjectOXIDATIVE STRESS-
dc.subjectMOUSE MODEL-
dc.subjectSCHIZOPHRENIC-PATIENTS-
dc.subjectCHROMOSOME 21Q22.3-
dc.subjectPREFRONTAL CORTEX-
dc.subjectMOOD DISORDERS-
dc.subjectMANIC SYMPTOMS-
dc.subjectFRONTAL-CORTEX-
dc.subjectANIMAL-MODELS-
dc.subjectADP-RIBOSE-
dc.titleTRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain-
dc.typeArticle-
dc.identifier.wosid000362501900006-
dc.identifier.scopusid2-s2.0-84940398568-
dc.type.rimsART-
dc.citation.volume35-
dc.citation.issue34-
dc.citation.beginningpage11811-
dc.citation.endingpage11823-
dc.citation.publicationnameJOURNAL OF NEUROSCIENCE-
dc.identifier.doi10.1523/JNEUROSCI.5251-14.2015-
dc.contributor.localauthorJeon, Daejong-
dc.contributor.nonIdAuthorJang, Yongwoo-
dc.contributor.nonIdAuthorLee, Sung Hoon-
dc.contributor.nonIdAuthorLee, Byeongjun-
dc.contributor.nonIdAuthorUchida, Kunitoshi-
dc.contributor.nonIdAuthorTominaga, Makoto-
dc.contributor.nonIdAuthorOh, Uhtaek-
dc.type.journalArticleArticle-
dc.subject.keywordAuthorbipolar disorder-
dc.subject.keywordAuthorcalcineurin-
dc.subject.keywordAuthorglycogen synthase kinase-3-
dc.subject.keywordAuthormutation-
dc.subject.keywordAuthorsusceptibilty-
dc.subject.keywordAuthorTRPM2-
dc.subject.keywordPlusOXIDATIVE STRESS-
dc.subject.keywordPlusMOUSE MODEL-
dc.subject.keywordPlusSCHIZOPHRENIC-PATIENTS-
dc.subject.keywordPlusCHROMOSOME 21Q22.3-
dc.subject.keywordPlusPREFRONTAL CORTEX-
dc.subject.keywordPlusMOOD DISORDERS-
dc.subject.keywordPlusMANIC SYMPTOMS-
dc.subject.keywordPlusFRONTAL-CORTEX-
dc.subject.keywordPlusANIMAL-MODELS-
dc.subject.keywordPlusADP-RIBOSE-
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