Yu Hu1, Xiao-Yue Hong1, Xi-Fei Yang2, Rong-Hong Ma3, Xin Wang1, Jun-Fei Zhang1, Qiong Feng1, Xiao-Guang Li1, Dong-Sheng Sun1, Xiao Li1, Hua-Li Wan1, Ting Li1, Qun Wang1, Dan Ke1, Jian-Zhi Wang4, Gong-Ping Liu5. 1. Department of Pathophysiology, Key Laboratory of Ministry of Education of China for Neurological Disorders, School of Basic Medicine of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. 2. Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Center for Disease Control and Prevention, No.8, Longyuan Road, Nanshan District, Shenzhen 518055, China. 3. Department of Laboratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. 4. Department of Pathophysiology, Key Laboratory of Ministry of Education of China for Neurological Disorders, School of Basic Medicine of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. Electronic address: wangjz@mail.hust.edu.cn. 5. Department of Pathophysiology, Key Laboratory of Ministry of Education of China for Neurological Disorders, School of Basic Medicine of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. Electronic address: liugp111@mail.hust.edu.cn.
Abstract
BACKGROUND: Maternal immune activation (MIA) is an independent risk factor for psychiatric disorders including depression spectrum in the offsprings, but the molecular mechanism is unclear. Recent studies show that interferon-stimulated gene-15 (ISG15) is involved in inflammation and neuronal dendrite development; here we studied the role of ISG15 in MIA-induced depression and the underlying mechanisms. METHODS: By vena caudalis injecting polyinosinic: polycytidylic acid (poly I:C) into the pregnant rats to mimic MIA, we used AAV or lentivirus to introduce or silence ISG15 expression. Synaptic plasticity was detected by confocal microscope and Golgi staining. Cognitive performances of the offspring were measured by Open field, Forced swimming and Sucrose preference test. RESULTS: We found that MIA induced depression-like behaviors with dendrite impairments in the offspring with ISG15 level increased in the offsprings' brain. Overexpressing ISG15 in the prefrontal cortex of neonatal cubs (P0) could mimic dendritic pathology and depressive like behaviors, while downregulating ISG15 rescued these abnormalities in the offsprings. Further studies demonstrated that MIA-induced upregulation of inflammatory cytokines promoted ISG15 expression in the offspring' brain which suppressed Rap2A ubiquitination via NEDD4 and thus induced Rap2A accumulation, while upregulating NEDD4 abolished ISG15-induced dendrite impairments. CONCLUSIONS: These data reveal that MIA impedes offsprings' dendrite development and causes depressive like behaviors by upregulating ISG15 and suppressing NEDD4/Rap2A signaling. The current findings suggest that inhibiting ISG15 may be a promising intervention of MIA-induced psychiatric disorders in the offsprings.
BACKGROUND: Maternal immune activation (MIA) is an independent risk factor for psychiatric disorders including depression spectrum in the offsprings, but the molecular mechanism is unclear. Recent studies show that interferon-stimulated gene-15 (ISG15) is involved in inflammation and neuronal dendrite development; here we studied the role of ISG15 in MIA-induced depression and the underlying mechanisms. METHODS: By vena caudalis injecting polyinosinic: polycytidylic acid (poly I:C) into the pregnant rats to mimic MIA, we used AAV or lentivirus to introduce or silence ISG15 expression. Synaptic plasticity was detected by confocal microscope and Golgi staining. Cognitive performances of the offspring were measured by Open field, Forced swimming and Sucrose preference test. RESULTS: We found that MIA induced depression-like behaviors with dendrite impairments in the offspring with ISG15 level increased in the offsprings' brain. Overexpressing ISG15 in the prefrontal cortex of neonatal cubs (P0) could mimic dendritic pathology and depressive like behaviors, while downregulating ISG15 rescued these abnormalities in the offsprings. Further studies demonstrated that MIA-induced upregulation of inflammatory cytokines promoted ISG15 expression in the offspring' brain which suppressed Rap2A ubiquitination via NEDD4 and thus induced Rap2A accumulation, while upregulating NEDD4 abolished ISG15-induced dendrite impairments. CONCLUSIONS: These data reveal that MIA impedes offsprings' dendrite development and causes depressive like behaviors by upregulating ISG15 and suppressing NEDD4/Rap2A signaling. The current findings suggest that inhibiting ISG15 may be a promising intervention of MIA-induced psychiatric disorders in the offsprings.