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

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          Abstract

          Bipolar 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 Ca(2+)-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 Ca(2+)-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.

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          Author and article information

          Journal
          J. Neurosci.
          The Journal of neuroscience : the official journal of the Society for Neuroscience
          Society for Neuroscience
          1529-2401
          0270-6474
          Aug 26 2015
          : 35
          : 34
          Affiliations
          [1 ] Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
          [2 ] Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
          [3 ] Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
          [4 ] Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea, and utoh@snu.ac.kr clark.jeon@gmail.com.
          [5 ] Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea, Institut Pasteur Korea, Sungnam-Si, Gyunggi-Do 463-400, Republic of Korea utoh@snu.ac.kr clark.jeon@gmail.com.
          Article
          35/34/11811
          10.1523/JNEUROSCI.5251-14.2015
          26311765

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