Effects of LPS-induced maternal immune activation on expression of autism-linked genes and autism-like behaviours in neonates and adulthood. Towards a maternal infection model of idiopathic autism

Abstract

Epidemiological studies have revealed a link between maternal immune activation (MIA) and autism-spectrum disorder (ASD) risk. In support of this, the offspring of dams exposed to LPS during pregnancy develop ASD-like behaviours that persisted into adulthood. To date, the liter-ature has primarily focused on the effects of LPS-MIA in adult male mice; there are few reports describing the behavioural effects of LPS-MIA in female mice, especially early in development. Further, the involvement of the mammalian target of rapamycin (mTOR) signaling pathway, which integrates both the humoral and cellular immune response, and a risk factor for ASD, has not been studied in this model. In the current study, we injected pregnant C57BL/6J mice with 75µg/kg of LPS on embryonic day 11.5 and 12. Male and female offspring were tested during development and at adulthood for the three core symptoms of ASD: social communica-tion, social interaction, and repetitive behaviours. Additionally, the expression, protein abun-dance and activity-induced phosphorylation of mTOR and its downstream effect on post-synaptic density 95 (PSD95) was analysed in hippocampal and cortical areas of offspring at postnatal day zero (P0) and at P130. Lastly, the hippocampal expression of Mtor in the LPS-MIA model was compared to the valproic acid (VPA) model of ASD. Female LPS-MIA mice displayed an impairment in social communication as displayed by a reduced number of USVs emitted at P8, and male LPS-MIA mice displayed deficits in social exploration and restrictive and repetitive behaviours in adulthood displayed by reduced response to social odours in the olfactory habituation/dishabituation task and increased grooming. A reduction in Mtor expres-sion was observed in the P0 hippocampus which was associated with an increase in phosphory-lated mTOR(ser2481). At P130 there was a reduction in mTOR activity resulting in reduced PSD95 in the ventral and dorsal hippocampus. In the VPA model, an increase in Mtor gene expression was observed, which was previously associated with reduced mTOR activity similar to the P130 LPS-MIA hippocampus. Overall, novel sex- and age- specific insights were observed behaviourally and in the mTOR pathway in the LPS-MIA model of ASD, comparable to the VPA model and idiopathic ASD, furthering our understanding of ASD and developing new avenues of future research.