Zhang Haiwang, Ben Zablah Youssif, Zhang Haorui, Liu An, Gugustea Radu, Lee Dongju, Luo Xiao, Meng Yanghong, Li Song, Zhou Changxi, Xin Tao, Jia Zhengping
Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Neurosurgery, Jinan, China.
Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada.
Front Aging Neurosci. 2022 Jul 22;14:914491. doi: 10.3389/fnagi.2022.914491. eCollection 2022.
Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer's disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear. In this study, we used local injections of AAV virus containing a dominant-negative (DN) Rac1 under the control of CaMKIIα promoter and found that the reduction of Rac1 hyperactivity in ventral hippocampal excitatory neurons improves social recognition memory in APP/PS1 mice. Expression of DN Rac1 also improves long-term potentiation, a key synaptic mechanism for memory formation. Our results suggest that overactivation of Rac1 in hippocampal excitatory neurons contributes to social memory deficits in APP/PS1 mice and that manipulating Rac1 activity may provide a potential therapeutic strategy to treat social deficits in AD.
Rac1在肌动蛋白细胞骨架、神经元结构、突触可塑性和记忆的调节中起着关键作用。在阿尔茨海默病（AD）的人类患者和动物模型中，已报道Rac1过度激活，并导致其空间记忆缺陷，但Rac1失调在其他形式的记忆缺陷中是否也很重要尚不清楚。此外，所涉及的细胞类型和突触机制仍不清楚。在本研究中，我们使用在CaMKIIα启动子控制下局部注射含有显性负性（DN）Rac1的腺相关病毒（AAV），发现腹侧海马兴奋性神经元中Rac1过度活性的降低改善了APP/PS1小鼠的社会识别记忆。DN Rac1的表达也改善了长时程增强，这是记忆形成的关键突触机制。我们的结果表明，海马兴奋性神经元中Rac1的过度激活导致APP/PS1小鼠的社会记忆缺陷，并且操纵Rac1活性可能为治疗AD中的社会缺陷提供一种潜在的治疗策略。
