Deficiency in the Inhibitory Serine-Phosphorylation of Glycogen Synthase Kinase-3 Increases Sensitivity to Mood Disturbances

被引：190
作者：
Polter, Abigail [1 ,2 ]
Beurel, Eleonore [1 ]
Yang, Sufen [1 ]
Garner, Rakesha [1 ]
Song, Ling [1 ]
Miller, Courtney A. [2 ]
Sweatt, J. David [2 ]
McMahon, Lori [2 ,3 ]
Bartolucci, Alfred A. [4 ]
Li, Xiaohua [2 ]
Jope, Richard S. [1 ]
机构：
[1] Univ Alabama, Dept Psychiat & Behav Neurobiol, Birmingham, AL 35294 USA
[2] Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA
[3] Univ Alabama, Dept Physiol & Biophys, Birmingham, AL 35294 USA
[4] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA
来源：
NEUROPSYCHOPHARMACOLOGY | 2010年 / 35卷 / 08期
关键词：
bipolar disorder; glycogen synthase kinase-3; depression; amphetamine; lithium; ASSESSING ANTIDEPRESSANT ACTIVITY; FORCED SWIM TEST; BIPOLAR DISORDER; ALZHEIMERS-DISEASE; PSYCHOTROPIC-DRUGS; RAT HIPPOCAMPUS; GENE-EXPRESSION; PROTEIN-LEVELS; MOUSE MODEL; DEPRESSION;
D O I：
10.1038/npp.2010.43
中图分类号：
Q189 [神经科学];
学科分类号：
071006 ;
摘要：
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. Neuropsychopharmacology (2010) 35, 1761-1774; doi:10.1038/npp.2010.43; published online 31 March 2010
引用
收藏
页码：1761 / 1774
页数：14
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