Sex-Specific, Intermediate Behavioral Phenotypes in Heterozygous Dopamine Transporter Mutant DAT T356M Mice

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with both genetic and environmental contributions. Previous work identified a de novo mutation in the dopamine transporter (DAT T356M) in an autism proband that results in profound behavioral changes when expressed homozygously in mice. Since complex human genetics are more likely to be present as heterozygous (single allele) mutations, we characterized mice that were heterozygous for the mutation. Both male and female DAT T356M^+/- mice exhibited hyperactivity but normal habituation to novel environments. The difference in hyperactivity compared to wild-type littermates was dramatically smaller than previously reported in homozygous animals. Other behavioral alterations were sex-specific, with only male heterozygous mice exhibiting greater repetitive behaviors and impaired spatial learning in the Barnes maze. Sensorimotor gating measured by prepulse inhibition of the startle response was largely unchanged in both sexes. Motor performance on the rotarod showed opposing effects, with male heterozygotes showing decreased latency to fall while females demonstrated increased latency (i.e., enhanced performance). These findings suggest that even a single copy of the DAT T356M variant can impact behavior in a sex-specific manner. The identification of intermediate phenotypes makes these mice an appropriate model for future studies examining how environmental factors might interact with genetic susceptibility to influence autism-relevant behaviors, particularly in the context of dopaminergic dysfunction.