Abstract # 3106 Sex-biased mitochondrial and behavioral alterations following early-life immune activation

Abstract

Autism Spectrum Disorders (ASDs) are a collection of complex neurodevelopmental disorders characterized by repetitive behavior and alterations in social interaction/communication. ASD occurs in 1 in 68 children in the US, with a strong sex bias in prevalence ( ∼ 4 males affected to every 1 female). Multiple reports have revealed pervasive immune and mitochondrial abnormalities in ASD patients. Increasing evidence suggests that mitochondrial function is inhibited during proinflammatory microglial activation, although no sex differences remain underexplored. Postmortem analyses of brains from children with ASD revealed significant decreases in expression of mitochondrial electron transport chain (ETC) subunits; however, analyses did not distinguish between cell type or sex. In an early-life immune activation (lipopolysaccharide;LPS) model of ASD, we isolated microglia from prefrontal cortex of PN30 mice. By PCR array, we found that ∼ 96% of mitochondrial ETC genes were strongly diminished by LPS in male microglia, while only ∼ 6% were similarly decreased in females, suggesting that reduced mitochondrial function may be implicated in microglial activation, particularly in males. We show that early-life LPS results in decreased social exploration in both males and females at PN15, but only increased latency to enter stranger bedding in male mice. By PN60, early-life LPS treatment resulted in decreased sociability and social novelty seeking in males only. These data indicate sex-biased deficits in social interaction and anxiety that are related to clinical manifestations of ASD.