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

Scientists studied mice with a gene change found in a person with autism. Mice with one copy of this gene change showed mild hyperactivity in both males and females. However, only male mice had problems with repetitive behaviors and learning spatial tasks, while female mice actually performed better on balance tests. This shows that even one copy of certain gene changes can affect behavior differently in males versus females.

This study investigated behavioral effects of a heterozygous dopamine transporter mutation (DAT T356M) previously identified in an autistic individual. Researchers examined mice carrying one copy of this mutation, finding both sexes showed hyperactivity but with milder effects than previously observed in mice with two copies. Male mice specifically exhibited increased repetitive behaviors and impaired spatial learning, while females showed enhanced motor performance on rotarod testing. Sensorimotor gating remained largely normal in both sexes.

These findings demonstrate that single-copy genetic variants can produce sex-specific behavioral changes relevant to autism, providing a model for studying gene-environment interactions in dopaminergic dysfunction.

Single-copy dopamine transporter variants may contribute to sex-specific autism behaviors. Findings support investigating gene-environment interactions and considering sex differences in autism research and potentially in clinical assessment approaches.

Sample size not reported. Single genetic model may not represent broader autism genetics. Behavioral assessments limited to specific paradigms. Environmental factors not examined despite being highlighted as future research direction.

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 T356Mmice 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.