Abstract
Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment, including Alzheimer’s disease and schizophrenia. Cognitive dysfunction is also characterized by the dysregulation of neuronal oscillatory activity, macroscopic electrical rhythms in brain that are critical to systems communication. A direct functional relationship between GSK-3β and neuronal oscillations has not been elucidated. Therefore, in the present study, using an adeno-associated viral vector containing a persistently active mutant form of GSK-3β, GSK-3β(S9A), the impact of elevated kinase activity in prefrontal cortex (PFC) or ventral hippocampus (vHIP) of rats on neuronal oscillatory activity was evaluated. GSK-3β(S9A)-induced changes in learning and memory were also assessed and the phosphorylation status of tau protein, a substrate of GSK-3β, examined. It was demonstrated that increasing GSK-3β(S9A) activity in either the PFC or vHIP had similar effects on neuronal oscillatory activity, enhancing theta and/or gamma spectral power in one or both regions. Increasing PFC GSK-3β(S9A) activity additionally suppressed high gamma PFC–vHIP coherence. These changes were accompanied by deficits in recognition memory, spatial learning, and/or reversal learning. Elevated pathogenic tau phosphorylation was also evident in regions where GSK-3β(S9A) activity was upregulated. The neurophysiological and learning and memory deficits induced by GSK-3β(S9A) suggest that aberrant GSK-3β signalling may not only play an early role in cognitive decline in Alzheimer’s disease but may also have a more central involvement in disorders of cognitive dysfunction through the regulation of neurophysiological network function.
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Data Availability
The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.
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This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (#401359) and the Weston Family Foundation (to MLP).
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AA performed the experiments, analysed the data, and assisted writing the manuscript. OW assisted performing experiments. MP designed the study, assisted with the data analysis, and contributed to writing the manuscript. All authors read and approved the final manuscript.
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All procedures complied with the guidelines described in the Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care, 1993) and the Animal Care Committee at the University of Guelph.
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Albeely, A.M., Williams, O.O.F. & Perreault, M.L. GSK-3β Disrupts Neuronal Oscillatory Function to Inhibit Learning and Memory in Male Rats. Cell Mol Neurobiol 42, 1341–1353 (2022). https://doi.org/10.1007/s10571-020-01020-z
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DOI: https://doi.org/10.1007/s10571-020-01020-z