Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-Induced Depression-Like Behavior in Mice

 Zhixin Peng1,2 • Xiaoheng Li2 • Jun Li3 • Yuan Dong4 • Yuhao Gao2 • Yajin Liao5 • Meichen Yan5 • Zengqiang Yuan1,2,5 • Jinbo Cheng5
1 Institute of Neuroscience, Hengyang Medical College, University of South China, Hengyang 421001, China 
2 The Brain Science Center, Beijing Institute of Basic Medical Sciences, 27 Taiping Road, Haidian District, Beijing 100850, China 
3 Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China 
4 Institutes of Brain Sciences and Disease, Medical College, Qingdao University, Qingdao 266071, China 
5 Center on Translational Neuroscience, College of Life and Environmental Science, Minzu University of China, Beijing 100081, China
Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression. Discs large homolog 1 (Dlg1), an adaptor protein, regulates cell polarization and the function of K? channels, which are reported to regulate the activation of microglia. However, little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis. In this study, we found that Dlg1 knockdown suppressed lipopolysaccharide (LPS)-induced inflammation by downregulating the activation of nuclear factor-jB signaling and the mitogen-activated protein kinase pathway in microglia. Moreover, using an inducible Dlg1 microglia-specific knockout (Dlg1flox/flox; CX3CR1CreER) mouse line, we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depressionlike behavior. In summary, our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.
Dlg1; Microglia; Neuroinflammation;Depression