Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada.
Collaborative Neuroscience Program, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada.
Cell Mol Neurobiol. 2022 Jul;42(5):1341-1353. doi: 10.1007/s10571-020-01020-z. Epub 2021 Jan 3.
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.
糖原合酶激酶-3β（GSK-3β）活性的改变与认知障碍障碍有关，包括阿尔茨海默病和精神分裂症。认知功能障碍的特征还在于神经元振荡活动的失调，即大脑中的宏观电节律，这对系统通信至关重要。GSK-3β 和神经元振荡之间的直接功能关系尚未阐明。因此，在本研究中，使用含有持续激活的 GSK-3β 突变形式的腺相关病毒载体，GSK-3β（S9A），评估了大鼠前额叶皮层（PFC）或腹侧海马（vHIP）中升高的激酶活性对神经元振荡活动的影响。还评估了 GSK-3β（S9A）诱导的学习和记忆变化，并检查了 GSK-3β 的磷酸化状态，tau 蛋白是 GSK-3β 的底物。结果表明，PFC 或 vHIP 中 GSK-3β（S9A）活性的增加对神经元振荡活动具有相似的影响，在一个或两个区域增强了θ和/或γ频谱功率。增加 PFC GSK-3β（S9A）活性还抑制了 PFC-vHIP 的高伽马相干性。这些变化伴随着识别记忆、空间学习和/或反转学习的缺陷。在 GSK-3β（S9A）活性上调的区域也明显出现了致病性 tau 磷酸化升高。GSK-3β（S9A）诱导的神经生理学和学习记忆缺陷表明，异常的 GSK-3β 信号传导不仅可能在阿尔茨海默病的认知能力下降早期发挥作用，而且可能通过调节神经生理网络功能在认知功能障碍中发挥更核心的作用。
