Methionine oxidation of actin cytoskeleton attenuates traumatic memory retention via reactivating dendritic spine morphogenesis
Cun-Dong Huang,
Yu Shi,
Fang Wang,
Peng-Fei Wu,
Jian-Guo Chen
Affiliations
Cun-Dong Huang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
Yu Shi
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
Fang Wang
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Hubei Shizhen Laboratory, Wuhan, Hubei, 430030, China; Corresponding author. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei, 430030, China.
Peng-Fei Wu
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Hubei Shizhen Laboratory, Wuhan, Hubei, 430030, China; Corresponding author. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei, 430030, China.
Jian-Guo Chen
Department of Pharmacology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, Hubei, 430030, China; The Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Hubei Shizhen Laboratory, Wuhan, Hubei, 430030, China; Corresponding author. 13 Hangkong Road, Qiaokou District, Wuhan, Hubei, 430030, China.
Post-traumatic stress disorder (PTSD) is characterized by hypermnesia of the trauma and a persistent fear response. The molecular mechanisms underlying the retention of traumatic memories remain largely unknown, which hinders the development of more effective treatments. Utilizing auditory fear conditioning, we demonstrate that a redox-dependent dynamic pathway for dendritic spine morphogenesis in the basolateral amygdala (BLA) is crucial for traumatic memory retention. Exposure to a fear-induced event markedly increased the reduction of oxidized filamentous actin (F-actin) and decreased the expression of the molecule interacting with CasL 1 (MICAL1), a methionine-oxidizing enzyme that directly oxidizes and depolymerizes F-actin, leading to cytoskeletal dynamic abnormalities in the BLA, which impairs dendritic spine morphogenesis and contributes to the persistence of fearful memories. Following fear conditioning, overexpression of MICAL1 in the BLA inhibited freezing behavior during fear memory retrieval via reactivating cytokinesis, whereas overexpression of methionine sulfoxide reductase B 1, a key enzyme that reduces oxidized F-actin monomer, increased freezing behavior during retrieval. Notably, intra-BLA injection of semaphorin 3A, an endogenous activator of MICAL1, rapidly disrupted fear memory within a short time window after conditioning. Collectively, our results indicate that redox modulation of actin cytoskeleton in the BLA is functionally linked to fear memory retention and PTSD-like memory.
