Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity

Haiwang Zhang; Youssif Ben Zablah; Haorui Zhang; An Liu; Radu Gugustea; Dongju Lee; Xiao Luo; Yanghong Meng; Song Li; Changxi Zhou; Tao Xin; Zhengping Jia

doi:10.3389/fnagi.2022.914491

Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity

Front Aging Neurosci. 2022 Jul 22:14:914491. doi: 10.3389/fnagi.2022.914491. eCollection 2022.

Authors

Haiwang Zhang^{1

2

3}, Youssif Ben Zablah^{2

3}, Haorui Zhang^{2

3}, An Liu⁴, Radu Gugustea^{2

3}, Dongju Lee^{2

3}, Xiao Luo^{2

3}, Yanghong Meng^{2

3}, Song Li⁵, Changxi Zhou⁶, Tao Xin¹, Zhengping Jia^{2

3}

Affiliations

¹ 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.
² Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, Canada.
³ Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
⁴ The Key Laboratory of Developmental Genes and Human Disease, Ministry of Education, School of Life Sciences and Technology, Southeast University, Nanjing, China.
⁵ Department of Neurosurgery, Caoxian People's Hospital, Caoxian, China.
⁶ Department of Geriatrics, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Beijing, China.

Abstract

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.

Keywords: APP/PS1 mouse model; LTP; Rac1; social memory; ventral hippocampus.