RT Journal Article SR Electronic T1 TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 11811 OP 11823 DO 10.1523/JNEUROSCI.5251-14.2015 VO 35 IS 34 A1 Yongwoo Jang A1 Sung Hoon Lee A1 Byeongjun Lee A1 Seungmoon Jung A1 Arshi Khalid A1 Kunitoshi Uchida A1 Makoto Tominaga A1 Daejong Jeon A1 Uhtaek Oh YR 2015 UL http://www.jneurosci.org/content/35/34/11811.abstract AB 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 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.SIGNIFICANCE STATEMENT Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium, a primary medicine for treating BD. Therefore, abnormal regulation of GSK-3 by hypoactive TRPM2 mutants accounts for the pathology of BD, providing the possible link between BD and TRPM2.