Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice |
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| Affiliation: | 1. Department of Psychiatry (UPK), University of Basel, Switzerland;2. Department of Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim/Heidelberg University, Germany;3. Department of Biomedicine, University Hospital Basel, Switzerland;4. Department of Neurosurgery, University Hospital Basel, Switzerland;1. Department of Pathology, Institute of Neuroscience, Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China;2. Institute of Neuroscience, Chongqing Medical University, Chongqing 400016, China;3. Chongqing Key Laboratory of Neurobiology, Chongqing Medical University, Chongqing 400016, China;4. Department of Geriatrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China;1. Grupos de Neurociencias y Muerte Celular, Instituto de Genética y Facultad de Medicina, Universidad Nacional de Colombia, Colombia;2. Area de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Calle 70, No. 52–21, Medellín, Universidad de Antioquia, Colombia;1. Department of Neurology, Xinqiao Hospital, The Army Medical University, Chongqing, China;2. Department of First Cadre Ward, The General Hospital of Northern Theater Command, Shenyang, Liaoning, China;3. Department of Neurology, The General Hospital of Northern Theater Command, Shenyang, Liaoning, China |
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| Abstract: | Depression is a long-lasting and persistent mood disorder in which the regulatory mechanisms of neuroinflammation are thought to play a contributing role to the physiopathology of the condition. Previous studies have shown that liver X receptors (LXRs) can regulate the activation of microglia and neuroinflammation. However, the role of LXRs in depression remains to be fully understood. In this study, we hypothesized that stress impairs the function of LXRs and that the LXRs agonist GW3965 plays a potential anti-depressive role by inhibiting neuroinflammation. The anti-depressive effects of GW3965 were evaluated in both chronic unpredictable mild stress (CUMS) and lipopolysaccharide (LPS) models. The LXRs antagonist GSK2033 was also employed to block LXRs. Behavioural tests were performed to measure depression-like phenotypes and learning abilities. Electrophysiological recordings and Golgi staining were used to measure the plasticity of the dentate gyrus synapse. The expression of synapse and neuroinflammation related proteins were evaluated by Western blotting and immunofluorescence. The activation of LXRs by GW3965 prevented emotional and cognitive deficits induced by either CUMS or LPS. GW3965 prevented the decreased level of LXR-β induced by CUMS. The activation of LXRs significantly improved the impairment of synaptic plasticity, prevented the up-regulation of inflammatory factors and inhibited NF-κB phosphorylation and microglial M1-polarization in both models. The antidepressive-like effects of GW3965 were blocked by GSK2033 in the CUMS and LPS models. Our data suggest that inhibition of the LXRs signalling pathway may be a key driver in the pathogenesis of neuroinflammation during depression and that LXRs agonists have a high potential in the treatment of depression. |
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| Keywords: | Liver X receptor Chronic unpredictable mild stress Lipopolysaccharide Neuroinflammation Synaptic plasticity Microglial M1-polarization |
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