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疾病有关，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，大脑中对系统通信至关重要的宏观电节律。GSK-3β 与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，使用含有持续活性突变形式的 GSK-3β、GSK-3β(S9A) 的腺相关病毒载体，前额叶皮层 (PFC) 或腹侧海马 (vHIP) 中激酶活性升高的影响评估了大鼠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以及 tau 蛋白的磷酸化状态，检查GSK-3β的底物。结果表明，增加 PFC 或 vHIP 中的 GSK-3β(S9A) 活性对神经元振荡活动具有相似的影响，增强一个或两个区域的 theta 和/或 gamma 光谱功率。增加 PFC GSK-3β(S9A) 活性还抑制了高伽马 PFC-vHIP 相干性。这些变化伴随着识别记忆、空间学习和/或逆向学习的缺陷。在 GSK-3β(S9A) 活性上调的区域，致病性 tau 磷酸化也很明显。