Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice.
Chronic unpredictable mild stress
Lipopolysaccharide
Liver X receptor
Microglial M1-polarization
Neuroinflammation
Synaptic plasticity
Journal
Brain, behavior, and immunity
ISSN: 1090-2139
Titre abrégé: Brain Behav Immun
Pays: Netherlands
ID NLM: 8800478
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
03
11
2020
revised:
05
02
2021
accepted:
24
02
2021
pubmed:
5
3
2021
medline:
28
5
2021
entrez:
4
3
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33662504
pii: S0889-1591(21)00091-X
doi: 10.1016/j.bbi.2021.02.026
pii:
doi:
Substances chimiques
Liver X Receptors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
111-124Informations de copyright
Copyright © 2021 Elsevier Inc. All rights reserved.