title: Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances.
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.
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
authors.forename: Abigail
authors.initials: A
authors.lastname: Polter
authors.forename: Eléonore
authors.initials: E
authors.lastname: Beurel
authors.forename: Sufen
authors.initials: S
authors.lastname: Yang
authors.forename: Rakesha
authors.initials: R
authors.lastname: Garner
authors.forename: Ling
authors.initials: L
authors.lastname: Song
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.forename: J David
authors.initials: JD
authors.lastname: Sweatt
authors.forename: Lori
authors.initials: L
authors.lastname: McMahon
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Bartolucci
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Richard S
authors.initials: RS
authors.lastname: Jope
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology; D004195:Disease Models, Animal; D004597:Electroshock / Q000009:adverse effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000378:metabolism*; D006380:Helplessness, Learned; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D019964:Mood Disorders / Q000235:genetics* / Q000503:physiopathology*; D010146:Pain / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism*; D013550:Swimming / Q000523:psychology
chemical_list: D012694:Serine; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha