Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring

Abstract

Environmental challenges to the maternal immune system during pregnancy have been associated with an increase in the frequency of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD) appearing in the offspring. Microglia, the brain’s resident immune-cells, are now known to be critically involved in normal brain development, shaping connections between neurons by pruning superfluous synaptic spines. Our aim was to investigate whether maternal infection during critical stages of gestation compromises the role of microglia in sculpting neuronal circuits. Using a mouse model of maternal immune activation (MIA) induced by bacterial Lipopolysaccharide (LPS), we assayed the offspring’s behavior during postnatal development. Additionally, we quantified spines within the offspring’s brain and assessed alterations in some molecular signals involved in pruning. LPS-induced MIA led to behavioral changes relevant to ASD in the offspring in the absence of gross neurological problems. Prenatal LPS resulted in a significant increase in the number of spines in the granule cells of the dentate gyrus, as well as a reduction in hippocampal expression of the fractalkine microglial receptor (CX3CR1), involved in mediating the pruning process in the offspring. Interestingly, these changes were only noted in the male progeny of the LPS challenged dams. These results provide an early indicator that microglial function is altered in the brain of offspring from immune challenged mothers and that the effects in the brain appear to be specific along sex lines.