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.