Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances

Abigail Polter, Eléonore Beurel, Sufen Yang, Rakesha Garner, Ling Song, Courtney A. Miller, J. David Sweatt, Lori McMahon, Alfred A. Bartolucci, Xiaohua Li, Richard S. Jope

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

Bipolar disorder, characterized by extreme manic and depressive moods, is a prevalent debilitating disease of unknown etiology. Because mood stabilizers, antipsychotics, antidepressants, and mood-regulating neuromodulators increase the inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3), we hypothesized that deficient GSK3 serine-phosphorylation may increase vulnerability to mood-related behavioral disturbances. This was tested by measuring behavioral characteristics of GSK3α/Β 21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3. GSK3 knockin mice displayed increased susceptibility to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Furthermore, serine-phosphorylation of GSK3 was reduced during both mood-related behavioral responses in wild-type mouse brain and in blood cells from patients with bipolar disorder. Therefore, proper control of GSK3 by serine-phosphorylation, which is targeted by agents therapeutic for bipolar disorder, is an important mechanism that regulates mood stabilization, and mice with disabled GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.

Original languageEnglish (US)
Pages (from-to)1761-1774
Number of pages14
JournalNeuropsychopharmacology
Volume35
Issue number8
DOIs
StatePublished - Jul 2010

Keywords

  • Amphetamine
  • Bipolar disorder
  • Depression
  • Glycogen synthase kinase-3
  • Lithium

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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    Polter, A., Beurel, E., Yang, S., Garner, R., Song, L., Miller, C. A., Sweatt, J. D., McMahon, L., Bartolucci, A. A., Li, X., & Jope, R. S. (2010). Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology, 35(8), 1761-1774. https://doi.org/10.1038/npp.2010.43