The Role And Mechanism Of Dlg1 In Microglial Activation Induced Neuroinflammation

Background:Dlg1,an adaptor protein,regulates cell polarization and the function of Kv1.3 potassium channel that is reported to regulate the activation of microglia.Microglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression.However,little is known about the role of Dlg1 in microglia and CNS homeostatic maintenance.Methods:In vitro,we generated BV2 knockdown and overexpressed Dlg1 cell line.LPS（1μg/μL）administration was utilized to establish inflammatory challenge.In vivo,we employed an inducible Dlg1microglia-specific knockout(Dlg1^flox/flox;CX3CR1^{cre ER})mouse line and utilized LPS（1 mg/kg）or Chronic restraint stress（CRS）to induce depression-like behavior,which was examined by behavioral performing（OFT,EPM,TST and FST）.Immunohistochemistry and immunofluorescence staining were used to study the numbers and morphologic changes in microglia.All genes expression changes in microglia were detected by quantitative real-time PCR.Results:We found that Dlg1 knockdown suppressed LPS-induced inflammation by downregulating the activation of NF-κB signaling and MAPK pathway in microglia.Microglial Dlg1 knockout reduced the activation of microglia and alleviated LPS or CRS induced depression-like behaviors in mice.Conclusions:Our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provided a potential therapeutic target for clinical treatment of depression.