Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances.
Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances.
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DOI：
10.1038/npp.2010.43
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发表时间：
2010-07
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影响因子：
--
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双相情感障碍，其特征是极端躁狂和抑郁情绪，是一种病因不明的普遍衰弱性疾病。由于情绪稳定剂、抗精神病药、抗抑郁药和情绪调节神经调节剂增加糖原合成酶激酶-3（GSK 3）的抑制性丝氨酸磷酸化，我们假设GSK 3丝氨酸磷酸化缺陷可能增加对情绪相关行为障碍的易感性。这通过测量具有丝氨酸至丙氨酸突变的GSK 3 α/β 21 A/21 A/9A/9A敲入小鼠的行为特征来测试，以阻断GSK 3的抑制性丝氨酸磷酸化。GSK 3基因敲入小鼠表现出对苯丙胺诱导的多动症和应激诱导的抑郁样行为的易感性增加。此外，在野生型小鼠脑和双相情感障碍患者血细胞中，GSK 3的丝氨酸磷酸化在与情绪相关的行为反应中均降低。因此，通过丝氨酸磷酸化适当控制GSK 3，这是双相情感障碍治疗药物的靶点，是调节情绪稳定的重要机制，GSK 3丝氨酸磷酸化障碍的小鼠可能为研究双相情感障碍提供有价值的模型。
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 GSK3α/β21A/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.
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DOI：
10.1017/s1461145704004535
发表时间：
2004-12-01
影响因子：
4.8
作者：
Gould, TD;Einat, H;Manji, HK
通讯作者：
Manji, HK
影响因子：
7.6
作者：
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通讯作者：
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影响因子：
10.6
作者：
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通讯作者：
Duman, Ronald S.
影响因子：
3.6
作者：
Crowley, JJ;Jones, MD;Lucki, I
通讯作者：
Lucki, I
影响因子：
10.6
作者：
Eom, Tae-Yeon;Jope, Richard S.
通讯作者：
Jope, Richard S.