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Sex-Specific, Intermediate Behavioral Phenotypes in Heterozygous Dopamine Transporter Mutant DAT T356M Mice
Emma Harris1, Krista C Paffenroth2, Adriana A Tienda3
1Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee, USA.
Genes, Brain, and Behavior
|November 23, 2025
Summary
A single copy of the autism-linked DAT T356M mutation in mice caused hyperactivity and sex-specific behavioral changes. This provides a new model for studying autism genetics and environmental interactions.
Area of Science:
- Neuroscience
- Genetics
- Behavioral Science
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by genetic and environmental factors.
- A de novo mutation in the dopamine transporter (DAT T356M) was previously found in an ASD patient, causing significant behavioral changes in homozygous mice.
Purpose of the Study:
- To investigate the behavioral effects of heterozygous (single allele) DAT T356M mutations in mice, as these are more common in human genetics.
- To characterize sex-specific behavioral alterations in mice carrying one copy of the DAT T356M variant.
Main Methods:
- Generation and behavioral testing of heterozygous DAT T356M mice (DAT T356M+/-).
- Assessment of hyperactivity, habituation, repetitive behaviors, spatial learning (Barnes maze), sensorimotor gating (prepulse inhibition), and motor performance (rotarod).
Main Results:
- Heterozygous DAT T356M mice showed hyperactivity, but less pronounced than homozygous mice.
- Behavioral changes were sex-specific: males exhibited increased repetitive behaviors and impaired spatial learning.
- Motor performance on the rotarod differed by sex, with males showing decreased and females showing increased performance.
Conclusions:
- A single copy of the DAT T356M variant can influence behavior in a sex-specific manner.
- These heterozygous mice represent a valuable model for exploring gene-environment interactions in ASD, particularly concerning dopaminergic dysfunction.
