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Neuropsychopharmacology ; 35(8): 1761-74, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20357757

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 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.


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