Ketamine, a non-competitive N-methyl-D-aspartate acid (NMDA) receptor antagonist, produces rapid and sustained antidepressant actions, but the underlying molecular mechanism remains unclear. The CX3CL1/CX3CR1 signaling is closely related to mood disorders, and this study aims to investigate its role in ketamine's antidepressant actions. We pharmacologically (AZD8797, a selective CX3CR1 antagonist) and genetically (intra-mPFC microinjection with AAV-CX3CR1-siRNA) manipulated the CX3CL1/CX3CR1 signaling and investigated their effects on ketamine's antidepressant-like effects in mice treated with corticosterone (Cort), and observed changes in synaptic plasticity in response to these manipulations. We found that 24 h after drug injection, ketamine (10 mg/kg, i.p.) significantly reversed the Cort-induced depression-like behaviors, and inhibited the overexpression of pro-inflammatory cytokines and microglial activation. Ketamine significantly improved the Cort-induced impairment in the dendritic complexity and spine densities. In addition, our ELISA results showed that ketamine significantly inhibited the activation of CX3CL1/CX3CR1 signaling, and ketamine attenuated the upregulation of CX3CR1 and CX3CL1 expression in Cort-treated HT22 and BV2 cells in vitro. Furthermore, pretreatment with AZD8797 (0.8 mg/kg, i.p., twice a week) completely blocked ketamine's antidepressant-like behavioral effects and eliminated ketamine-induced enhancement in the synaptic plasticity; intra-mPFC microinjection with AAV-CX3CR1-siRNA also prevented ketamine's behavioral effects and beneficial effects on the synaptic plasticity. These findings demonstrated that CX3CL1/CX3CR1 signaling-mediated synaptic plasticity played essential roles in ketamine's antidepressant-like effects, which opened a new door to targeting chemokines to improve depression symptoms.
BACKGROUND AND PURPOSE
Microglia are central regulators of neuroinflammation in depression. Drivers involved remain incompletely understood. Sigma non-opioid intracellular receptor 1 (S1R) is involved in brain inflammation. This study investigates how S1R regulates neuroinflammation associated with depression.
EXPERIMENTAL APPROACH
Using integrated machine learning and single-cell transcriptomics, a key gene implicated in microglial dysfunction in depression was identified. Its relevance was examined in a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-stimulated BV-2 cells. Further, targeted knockdown or overexpression of this gene was performed on medial prefrontal cortex (mPFC) microglia, followed by integrated behavioural, cellular and molecular analyses.
KEY RESULTS
Plxdc2 was the key gene up-regulated at both transcriptional and protein levels in blood and depression-susceptible brain regions. Single-cell RNA sequencing confirmed its specific enrichment in microglia, particularly within inflammatory gene sets related to N-linked glycosylation (NLG). LPS-treated mice, depressive-like behaviours were accompanied by elevated expression of Plxdc2 and the glycosylation-related enzyme β-1,4-galactosyltransferase 1 in mPFC microglia. The S1R agonist Hypidone hydrochloride (YL-0919) or conditional knockdown of Plxdc2, reversed these molecular changes, reduced neuroinflammation and alleviated depressive-like behaviours. Analysis demonstrated that overexpressing Plxdc2 in mPFC microglia activated the JAK2-STAT1 pathway, enhanced NLG, shifting microglia towards a pro-inflammatory phenotype, worsening deficits in synaptic plasticity and induced depressive-like behaviour. These were reversible by the NLG inhibitor tunicamycin.
CONCLUSIONS AND IMPLICATIONS
Plxdc2 promotes depressive-like behaviours by dysregulating NLG-mediated inflammatory in microglia. S1R activation has a therapeutic effect by inhibiting this pathway, positioning the S1R-Plxdc2 axis as a potential target for modulating microglial function in inflammation-related depression.
Jing-ya Wang, Peng Ren, De-yi Yang et al.· British Journal of Pharmacol...· 0 citations
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