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Xiaomei Zhong,1 Cong Ouyang,2 Wanyuan Liang,2 Cunying Dai,2 Weiru Zhang2 1Department of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of China; 2Institute of Neuroscience, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of ChinaCorrespondence: Xiaomei ZhongDepartment of Geriatric Psychiatry, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510370, People’s Republic of ChinaTel +8620-8126-8084Fax +8620-8189-1391Email lovlaugh@163.comPurpose: Learning impairment after electroconvulsive therapy (ECT) is common. Ketamine, an anesthetic used for ECT, has been demonstrated to attenuate cognitive impairment after ECT. However, the mechanism by which ketamine occurs in this case is still unknown. We aimed to explore the role of ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] in the protection against learning impairment and investigate whether autophagy is involved in the protective effect.Materials and Methods: A rat depression model received electroconvulsive shock (ECS; simulated ECT in animal models) daily for 3 days. The Morris water maze was used to assess the spatial learning function of the rats. Western blotting was used to detect the expression of Beclin-1, light chain (LC)3-II/LC3-I, p62, mammalian target of rapamycin (mTOR), and p-mTOR in the hippocampus.Results: The escape latency for the maze in the ECS group was significantly longer than that in the sham ECS group (P=0.042). Meanwhile, the escape latency in the (2R,6R)-HNK+ECS group was significantly shorter than that in the ECS group (P=0.005). The LC3-II/LC3-I ratio and Beclin-1 expression level significantly increased, and the p62 expression level significantly decreased in the ECS group, compared with those in the sham ECS group (all P< 0.001). The (2R,6R)-HNK+ECS group sho