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

Cited 26 time in webofscience Cited 0 time in scopus
  • Hit : 204
  • Download : 0
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.
Publisher
SOC NEUROSCIENCE
Issue Date
2015-08
Language
English
Article Type
Article
Keywords

OXIDATIVE STRESS; MOUSE MODEL; SCHIZOPHRENIC-PATIENTS; CHROMOSOME 21Q22.3; PREFRONTAL CORTEX; MOOD DISORDERS; MANIC SYMPTOMS; FRONTAL-CORTEX; ANIMAL-MODELS; ADP-RIBOSE

Citation

JOURNAL OF NEUROSCIENCE, v.35, no.34, pp.11811 - 11823

ISSN
0270-6474
DOI
10.1523/JNEUROSCI.5251-14.2015
URI
http://hdl.handle.net/10203/205384
Appears in Collection
BiS-Journal Papers(저널논문)
Files in This Item
There are no files associated with this item.
This item is cited by other documents in WoS
⊙ Detail Information in WoSⓡ Click to see webofscience_button
⊙ Cited 26 items in WoS Click to see citing articles in records_button

qr_code

  • mendeley

    citeulike


rss_1.0 rss_2.0 atom_1.0