Pardo M, Abrial E, Jope R S, Beurel E
Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, FL, USA.
Genes Brain Behav. 2016 Mar;15(3):348-55. doi: 10.1111/gbb.12283. Epub 2016 Feb 12.
Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3α or GSK3β knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3β, not GSK3α, knockin mice displayed heightened vulnerability to the learned helplessness model of depression-like behavior. Three cognitive measures impaired in GSK3α/β knockin mice showed differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3β, not in GSK3α, knockin mice, whereas temporal order memory was not impaired in GSK3α or GSK3β knockin mice, and co-ordinate spatial processing was impaired in both GSK3α and GSK3β knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3β knockin mice, but not impaired in GSK3α knockin mice. Increased activity of GSK3β, in the absence of overexpression or disease pathology, is sufficient to impair mood regulation, novel object recognition and hippocampal NPC proliferation, whereas hyperactive GSK3α individually does not impair these processes. These results show that hyperactivity of the two GSK3 isoforms execute non-redundant effects on these processes.
异常活跃的糖原合酶激酶-3（GSK3）在多种精神和神经疾病的病理过程中起作用。在小鼠模型中，这包括增加对情绪相关行为失调的易感性、损害多项认知任务的表现以及损害成年海马神经前体细胞（NPC）的增殖。这些缺陷在GSK3α/β基因敲入小鼠中都很明显，其中丝氨酸到丙氨酸的突变阻断了两种GSK3亚型的抑制性丝氨酸磷酸化调节，使GSK3处于过度活跃状态。目前尚不清楚这两种GSK3亚型在这些过程中是否执行冗余作用，或者一种GSK3亚型的过度活跃是否具有主要影响。为了验证这一点，我们检测了仅一种亚型突变为过度活跃形式的GSK3α或GSK3β基因敲入小鼠。只有GSK3β而非GSK3α基因敲入小鼠对抑郁样行为的习得性无助模型表现出更高的易感性。GSK3α/β基因敲入小鼠中受损的三项认知指标显示出GSK3亚型的差异调节。在GSK3β而非GSK3α基因敲入小鼠中，新物体识别受损，而在GSK3α或GSK3β基因敲入小鼠中时间顺序记忆未受损，并且在GSK3α和GSK3β基因敲入小鼠中协调空间处理均受损。成年海马NPC增殖在GSK3β基因敲入小鼠中严重受损，但在GSK3α基因敲入小鼠中未受损。在没有过表达或疾病病理的情况下，GSK3β活性增加足以损害情绪调节、新物体识别和海马NPC增殖，而单独过度活跃的GSK3α不会损害这些过程。这些结果表明，两种GSK3亚型的过度活跃对这些过程产生非冗余效应。
