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

Neuropsychopharmacology. 2010 Jul;35(8):1761-74. doi: 10.1038/npp.2010.43. Epub 2010 Mar 31.


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 GSK3 alpha/beta(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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Behavior, Animal
  • Conditioning, Psychological / physiology
  • Disease Models, Animal
  • Electroshock / adverse effects
  • Enzyme-Linked Immunosorbent Assay / methods
  • Exploratory Behavior / physiology
  • Fear
  • Female
  • Glycogen Synthase Kinase 3 / deficiency*
  • Glycogen Synthase Kinase 3 / metabolism*
  • Helplessness, Learned
  • Hippocampus / physiopathology
  • Humans
  • In Vitro Techniques
  • Long-Term Potentiation / genetics
  • Male
  • Maze Learning / physiology
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Mood Disorders / genetics*
  • Mood Disorders / physiopathology*
  • Pain / etiology
  • Pain / genetics
  • Pain / physiopathology
  • Pain Threshold / physiology
  • Phosphorylation
  • Serine / metabolism*
  • Swimming / psychology


  • Serine
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha