Activation of sigma non-opioid intracellular receptor 1 (S1R) receptor inhibits plexin domain containing 2 (Plxdc2) driven microglial inflammation to ameliorate depressive-like behaviours in mice.
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.