Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances.
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.
Polter
Abigail
A
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Beurel
Eléonore
E
Yang
Sufen
S
Garner
Rakesha
R
Song
Ling
L
Miller
Courtney A
CA
Sweatt
J David
JD
McMahon
Lori
L
Bartolucci
Alfred A
AA
Li
Xiaohua
X
Jope
Richard S
RS
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D012694:Serine; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha