Behavioral and molecular characterization of prenatal stress effects on the C57BL/6J genetic background for the study of autism spectrum disorder.

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from non-stressed dams. Adult mice born from prenatally restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from non-stressed (NS) control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nucleus accumbens and caudate-putamen via qRT-PCR. The male PRS mouse behavioral phenotype coincided with aberrant expression of glutamate and GABA marker genes (e.g., Grin1, Grin2b, Gls, Gat1, Reln) in neural substrates of social behavior. Rescue of the male PRS sociability deficit by a known antipsychotic with epigenetic properties (i.e., clozapine (5 mg/kg) + 18-hr washout) indicated possible epigenetic regulation of genes that govern sociability. Clozapine treatment increased the expression levels of genes involved in DNA methylation, histone methylation, and histone acetylation in the nucleus accumbens. Identification of etiology-specific mechanisms underlying clinically relevant behavioral phenotypes may ultimately provide novel therapeutic interventions for the treatment of psychiatric disorders including ASD. Significance Statement The effects of prenatal stress on the C57BL/6J mouse genetic background are incompletely understood with regard to adverse psychiatric outcomes and respective underlying molecular mechanisms. Considering the prominent use of C57BL/6J mice for the generation of preclinical models for the study of autism spectrum disorder (ASD) and putative differences in stress resiliency across mouse strains, this gap in knowledge is an obstacle to contextualizing prenatal stress as an ASD etiological risk factor within the broader ASD preclinical literature. This study expands current knowledge of the relationship between prenatal stress exposure and the later presentation of representative behaviors for ASD symptom domains, underlying changes in gene expression, and insight into the potential of alleviating ASD-like behaviors through epigenetic mechanisms.