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GSK3β isoform-selective regulation of depression, memory and hippocampal cell proliferation
M Pardo1,2, E Abrial1,2, R S Jope1,2
1Department of Psychiatry and Behavioral Sciences, University of Miami, Miami, FL, USA.
Abstract:
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.
Insights
Hyperactive glycogen synthase kinase-3 beta (GSK3β) significantly impacts mood regulation, memory, and neural precursor cell proliferation. Hyperactive GSK3α does not independently affect these processes, indicating non-redundant roles for GSK3 isoforms in neurological and psychiatric disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Psychiatry
Background:
- Abnormally active glycogen synthase kinase-3 (GSK3) is implicated in psychiatric and neurological disorders.
- GSK3 hyperactivity in mice leads to mood dysregulation, cognitive deficits, and impaired hippocampal neural precursor cell (NPC) proliferation.
- It was unclear if GSK3 isoforms (GSK3α and GSK3β) have redundant or distinct roles in these processes.
Purpose of the Study:
- To investigate the specific roles of GSK3α and GSK3β hyperactivity in mood regulation, cognitive function, and adult hippocampal NPC proliferation.
- To determine if the effects of GSK3 hyperactivity are isoform-specific or redundant.
Main Methods:
- Generation and analysis of GSK3α-specific and GSK3β-specific knockin mice with mutations rendering the respective isoform hyperactive.
- Assessment of depression-like behavior using the learned helplessness model.
- Evaluation of cognitive functions including novel object recognition, temporal order memory, and co-ordinate spatial processing.
- Quantification of adult hippocampal NPC proliferation.
Main Results:
- Only GSK3β hyperactivity, not GSK3α, increased vulnerability to learned helplessness (depression-like behavior).
- Novel object recognition was impaired by GSK3β hyperactivity, while co-ordinate spatial processing was impaired by both GSK3α and GSK3β hyperactivity.
- Adult hippocampal NPC proliferation was significantly impaired by GSK3β hyperactivity but not by GSK3α hyperactivity.
- Temporal order memory was not affected by hyperactivity of either isoform.
Conclusions:
- Hyperactivity of GSK3β alone is sufficient to impair mood regulation, novel object recognition, and hippocampal NPC proliferation.
- The two GSK3 isoforms (GSK3α and GSK3β) exert non-redundant effects on mood, cognition, and neurogenesis.
- These findings highlight GSK3β as a key player in the pathophysiology of certain neurological and psychiatric conditions.
