Modulation of Glutamate Release by Dexmedetomidine Preserves Dendritic Spines and Alleviates Cognitive Impairment in a Murine Model of Perioperative Neurocognitive Disorder
Yan Zhang1,2,3 · Junzhao Li4 · Xueju Wang5 · Zhongyu Zhang6 · Shuai Long4 · Chuanyu Edward Li4 · Yan Liu7 · John Man Tak Chu3 · Raymond Chuen‑Chung Chang8 · Gordon Tin‑Chun Wong3,9 · Yong Zhang4,10
1 State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China
2 Neuroscience Center, Chinese Academy of Medical Sciences, Beijing 100005, China
3 Department of Anaesthesiology, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
4 Neuroscience Research Institute and Department of Neurobiology, School of Basic Medical Sciences, Peking University, Key Laboratory for Neuroscience, Ministry of Education of China and National Health Commission of the People’s Republic of China, Beijing 100083, China
5 Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, China
6 Zhejiang Provincial Key Lab of Addiction Research, The Affiliated Kangning Hospital of Ningbo University, Ningbo 315201, China
7 Department of Rehabilitation, Shenzhen Nanshan People’s Hospital, Shenzhen 518052, China
8 Laboratory of Neurodegenerative Diseases, School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
9 Department of Anaesthesiology, The University of Hong Kong, Queen Mary Hospital, Hong Kong SAR, China
10 IDG/McGovern Institute for Brain Research at PKU, Beijing 100871, China
Abstract
Perioperative neurocognitive disorders (PNDs) represent a significant challenge in the perioperative setting, while the pathophysiology of PNDs remains unclear. Utilizing a murine model of abdominal surgery, we found that abnormal glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) and hippocampus contributes to postoperative cognitive impairments. Increases in the frequency of miniature excitatory postsynaptic currents in both the mPFC and CA1 neurons indicate enhanced presynaptic glutamate release while having little effect on inhibitory neurotransmission. Surgery also enhances glutamate release from presynaptic terminals in the Schaffer collateral pathway. In addition, abdominal surgery increased the activation of microglia and astrocytes, elevated central inflammatory markers, and reduced excitatory amino-acid transporter-2 expression. Dexmedetomidine significantly mitigates the postoperative cognitive deficits by reducing inflammation and preserving neuronal structural complexity and dendritic spine stability, likely through inhibiting glutamate release and enhancing its reuptake. These findings advance our understanding of the etiology of PNDs and provide hints for potential intervention.
Keywords
Hippocampus; Medial prefrontal cortex; Glutamate; Excitatory amino-acid transporter-2; Excitotoxicity; Dexmedetomidine
