Neonatal testosterone exposure modulates exploration and object avoidance without exacerbating autism-like behavior in Shank3b-deficient mice.

A rapid increase in autism spectrum disorder (ASD) prevalence, high heritability, and higher incidence in boys suggest a role of gene-environment interactions, likely involving sex hormones in its etiology. Prenatal exposure to high testosterone concentration has been linked to risk of ASD, however, experimental proof in genetically predisposed animals is lacking. Since neonatal development in mice mirrors late prenatal neurodevelopment in humans, we investigated the effects of neonatal testosterone administration on the behavior of female and male Shank3b(-/-) mice. On postnatal day 1, neonate Shank3b(-/-) and wild-type pups of both sexes received a single dose of testosterone (1 mg) or vehicle subcutaneously. Behavioral phenotyping of mice was conducted in adolescence and adulthood. ASD-like behavior was unaffected by the combination of neonatal exposure to testosterone, male sex, and Shank3b deficiency in both adolescence and adulthood. In adolescence, testosterone-treated mice showed 32% higher object-avoidance behavior in comparison to control mice. Shank3b(-/-) mice spent threefold longer time self-grooming, buried half as many marbles, and vertically explored 23% less than wild-type mice. In adulthood, neonatal exposure to testosterone reduced vertical exploration by 34% and locomotor activity by 15%. Shank3b(-/-) mice self-groomed threefold longer, buried 31% fewer marbles, and spent 37% less time by vertical exploration than wild-type mice. Neonatal exposure to testosterone seems to affect object avoidance and exploration, rather than ASD-like behavior. Early testosterone exposure or its synergistic effects with sex and genetic predisposition on the ASD-like phenotype later in life seem to be limited.