Motor transitions’ peculiarity of heterozygous DAT rats when offspring of an unconventional KOxWT mating

Causal factors of psychiatric diseases are unclear, due to gene×environmentinteractions. Evaluation of consequences, after a dopamine-transporter (DAT) gene knock-out (DATKO),has enhanced understanding the pathological dynamics of several brain disorders, such asAttention-Deficit/Hyperactivity and Bipolar-Affective disorders. Recently, our attention has shiftedto DAT hypo-functional (heterozygous, HET) rodents: HET dams display less maternal care and HETfemales display marked hypo-locomotion if cared by HET dams (Mariano et al., 2019). We assessedphenotypes of male DAT-heterozygous rats as a function of their parents: we compared “maternal”origin (MAT-HET, obtained by breeding KO-male rats with WT-female dams) to “mixed” origin(MIX-HET, obtained by classical breeding, both heterozygous parents) of the allele. MAT-HETsubjects had significantly longer rhythms of daily locomotor activity than MIX-HET and WT-controlsubjects. Furthermore, acute methylphenidate (MPH: 0, 1, 2 mg/kg) revealed elevated threshold forlocomotor stimulation in MAT-HETs, with no response to the lower dose. Finally, by Porsolt-Test,MAT-HETs showed enhanced escape-seeking (diving) with more transitions towards behavioraldespair (floating). When comparing both MAT- and MIX-HET to WT-control rats, decreased levelsof DAT and HDAC4 were evident in the ventral-striatum; moreover, with respect to MIX-HETsubjects, MAT-HET ones displayed increased DAT density in dorsal-striatum. MAT-HET ratsdisplayed region-specific changes in DAT expression, compared to “classical” MIX-HET subjects:greater DAT availability may elevate threshold for dopamine action. Further behavioral andepigenetic characterizations of MAT-HETs, together with deeper characterization of maternal roles,could help to explore parent-of-origin mechanisms for such a peculiar phenotype.