The human gene SLC6A3 has been identified as a candidate susceptibility locus for autism spectrum disorder. SLC6A3 encodes a dopamine transporter that effects reuptake of the neurotransmitter at presynaptic terminals (a sodium:neurotransmitter symporter). There is a single orthologous dopamine transporter in Drosophila, Dmel\DAT, for which classical loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. Dmel\DAT is also orthologous to second gene in human, SLC6A2, which acts as a sodium:neurotransmitter symporter for norepinephrine in human. SLC6A3 is also implicated in infantile parkinsonism-dystonia (see FBhh0000749) and is postulated to be a susceptibility locus for development of ADHD (see FBhh0000654).
Multiple different UAS constructs of the human Hsap\SLC6A3 have been introduced into flies, including wild-type SLC6A3 and a gene carrying a mutational lesion implicated in autism spectrum disorder. Variant(s) implicated in human disease tested (as transgenic human gene, SLC6A3): the T356M and ΔN336 variant forms have been introduced into flies. Heterologous rescue (functional complementation) is observed: expression of wild-type SLC6A3 in dopaminergic neurons is able to rescue the hyperactive phenotype of a Dmel\DAT loss-of-function allele; expression of the T356M variant form of SLC6A3 also reduces the hyperactive phenotype, but to a significantly lesser extent. Using flies homozygous for a Dmel\DAT loss-of-function mutation, phenotypes of the ΔN336 Hsap\SLC6A3 variant, including dopamine uptake in the brain and various behavioral phenotypes, have been compared with those of the wild-type human gene.
Phenotypes of the original loss-of-function mutation of Dmel\DAT (DATfmn) include hyperactivity, sleep-defective phenotypes and locomotor-behavior-defective phenotypes. These phenotypes are relevant to modela of both autism and ADHD. Pan-neuronal knockdown of DAT, effected by RNAi, results in hyperactivity and sleep loss; the phenotypes are more pronounced during night. Feeding with the ADHD-ameliorating pharmaceutical MPH (methylphenidate) results in reduction of the hyperactivity and sleep phenotypes.
[updated May 2019 by FlyBase; FBrf0222196]