Inflammation-dependent ISG15 upregulation mediates MIA -induced dendrite damages and depression by disrupting NEDD4/Rap2A signaling

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Hu, Yu¹  Hong, Xiao-Yue¹  Yang, Xi-Fei²  Ma, Rong-Hong³  Wang, Xin¹  Zhang, Jun-Fei¹  Feng, Qiong¹  Li, Xiao-Guang¹  Sun, Dong-Sheng¹  Li, Xiao¹  Wan, Hua-Li¹  Li, Ting¹  Wang, Qun¹  Ke, Dan¹  Wang, Jian-Zhi^1,4  Liu, Gong-Ping^1,4 

[1] Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Basic Med, Dept Pathophysiol,Key Lab,Minist Educ China Neuro, Wuhan 430030, Hubei, Peoples R China

[2] Shenzhen Ctr Dis Control & Prevent, Key Lab Modern Toxicol Shenzhen, 8 Longyuan Rd, Shenzhen 518055, Peoples R China

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Union Hosp, Dept Lab Med, Wuhan 430022, Hubei, Peoples R China

[4] Nantong Univ, Coinnovat Ctr Neuroregenerat, Nantong 226001, Peoples R China

关键词: Maternal immune activation;    ISG15;    Offspring;    Dendrite development;    Depression;   

DOI  :  10.1016/j.bbadis.2019.02.020

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free