Impacts of an Autism-Linked Dopamine Transporter Variant on Brain and Behavior in a Murine Model

Abstract

The dopamine transporter (DAT), a presynaptic membrane protein, regulates the temporal and spatial availability of the neurotransmitter dopamine (DA). The precise regulation of synaptic DA by the DAT fine-tunes the phasic nature of the DA signal, which is required for reward learning and behavioral motivation. Dysregulation of the DA system has been implicated in various neuropsychiatric disorders, including Autism Spectrum Disorder (ASD). A de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was identified in an individual with ASD. Mice homozygous for this mutation (DAT T356M+/+ mice) were found to display significant impairments in the uptake of released DA and reduced total tissue content of DA. DAT T356M+/+ mice also exhibited a number of behavioral changes corresponding with the behavioral characteristics of ASD (including reduced social preference, repetitive behaviors, and profound increases in spontaneous locomotor activity). Antagonism of the DAT reduced the observed hyperlocomotion in DAT T356M+/+ animals, suggesting that DAT-mediated leak of DA may underlie hyperlocomotion in these animals.