Abstract
<title>Abstract</title> <p> Autism spectrum disorder (ASD) is increasingly associated with neuroimmune dysregulation, yet the molecular mechanisms coupling synaptic dysfunction to circuit pathology remain unclear. Here we show that the ASD-associated R451C mutation in the Neuroligin-3 ( <italic>Nlgn3</italic> ) gene induces a neuroinflammatory process in the striatum, sustained by failure of the pathway of resolution of inflammation. Integrated lipidomic and cytokine profiling revealed a marked imbalance in the striatum of ASD mice, characterized by an increase in pro-inflammatory arachidonic acid–derived eicosanoids and depletion of specialized pro-resolving mediators and their DHA/EPA precursors. The lipidomic dysregulation was accompanied by increased pro-inflammatory cytokines as well as defective anti-inflammatory counter-regulation. High-dimensional immunophenotyping uncovered a persistent shift of striatal microglia toward a pro-inflammatory, antigen-presenting state and a concomitant bias toward neurotoxic-like astrocytes. Importantly, eight weeks of environmental enrichment fully normalized lipid and cytokine signatures, and restored homeostatic glial phenotypes. Notably, the prolonged stimulation also rescued the corticostriatal synaptic plasticity deficits, and reversed social, motivational, repetitive, and motor abnormalities of R451C- <italic>Nlgn3</italic> mice. These findings suggest a defective regulation of the inflammation-resolution balance as a mechanistic bridge between ASD-linked postsynaptic gene mutations and circuit dysfunction and demonstrate that environmental enrichment can re-engage endogenous resolution pathways and restore striatal function and behavior. </p>