PPARγ–Wnt/β-catenin–HK2 axis associates with impaired neuroimmune homeostasis and metabolic dysregulation in MIA offspring

Abstract

Maternal immune activation (MIA) during gestation elevates the risk for autism spectrum disorder (ASD), but the underlying neurobiological mechanisms require further elucidation. Using a lipopolysaccharide (LPS)-induced MIA rat model, offspring exhibited specific behavioral alterations, including a lack of social preference in the three-chamber test and increased repetitive behaviors in the marble-burying test. Molecular analysis of the hippocampus revealed coordinated alterations, characterized by suppressed expression of peroxisome proliferator-activated receptor γ (PPARγ) alongside upregulated levels of β-catenin and hexokinase 2 (HK2). This was accompanied by a specific reduction in the hippocampal anti-inflammatory cytokine IL-10, suggesting a deficit in immune homeostasis. In primary microglia, LPS exposure recapitulated the suppression of PPARγ and induced metabolic alterations characterized by decreased ATP and increased lactate levels. Pharmacological activation of PPARγ with rosiglitazone partially reversed these molecular and metabolic alterations in vitro. Collectively, these findings suggest an association between dysregulation of the PPARγ–Wnt/β-catenin–HK2 axis, specific hippocampal neuroimmune shifts, and altered microglial metabolism in MIA offspring. The concordance between in vivo and in vitro observations implicates PPARγ signaling as a potential modulator of neuroimmune and metabolic pathways linked to MIA-related neurodevelopmental perturbations.