What is the role of glycogen synthase kinase 3-beta (GSK3?) in the pathophysiology of bipolar affective disorder (manic-depressive illness)?

Updated: May 30, 2019
  • Author: Stephen Soreff, MD; Chief Editor: Glen L Xiong, MD  more...
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Three of the other associated genes in this study also interact with the Wnt signaling pathway upstream and downstream of glycogen synthase kinase 3-beta (GSK3β). Lithium-mediated inhibition of GSK3β is thought to result in downregulation of molecules involved in cell death and upregulation of neuroprotective factors.

Additionally, GSK3β is a central regulator of the circadian clock, and lithium-mediated modulation of circadian periodicity is thought to be a critical component of lithium’s therapeutic effect. In fact, another major coup for bipolar disorder research has been the finding that a dominant-negative mutation in the CLOCK gene normally contributing to circadian periodicity in humans results in maniclike behavior in mice, [24] including hyperactivity, decreased sleep, reduced anxiety, and an increased response to cocaine. The latter finding also provides a shared biologic basis for the high rate of substance abuse observed in clinical populations of subjects with bipolar disorder.

Furthermore, the experimenters were able to abolish the manic behaviors by rescuing expression of normal CLOCK specifically in the ventral tegmental area of the mouse brain. [25] This area is rich in D2 receptors. Joseph Coyle hypothesized in his commentary in the paper on the same issue that the efficacy of atypical antipsychotics in acute mania might, in part, be achieved by their ability to lower activity in neurons specifically within the ventral tegmental area. [26]

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