TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brainopen access
- Authors
- Jang, Yongwoo; Lee, Sung Hoon; Lee, Byeongjun; Jung, Seungmoon; Khalid, Arshi; Uchida, Kunitoshi; Tominaga, Makoto; Jeon, Daejong; Oh, Uhtaek
- Issue Date
- Aug-2015
- Publisher
- Society for Neuroscience
- Keywords
- bipolar disorder; calcineurin; glycogen synthase kinase-3; mutation; susceptibilty; TRPM2
- Citation
- Journal of Neuroscience, v.35, no.34, pp.11811 - 11823
- Indexed
- SCIE
SCOPUS
- Journal Title
- Journal of Neuroscience
- Volume
- 35
- Number
- 34
- Start Page
- 11811
- End Page
- 11823
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/156557
- DOI
- 10.1523/JNEUROSCI.5251-14.2015
- ISSN
- 0270-6474
- 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 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.
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