Exploring transgenerational inheritance in epigenotypes of DAT heterozygous rats: circadian anomalies and attentional vulnerability

: Dopamine (DA) is mainly involved in locomotor activity, reward processes and maternal behaviors. Rats with KO gene for dopamine transporter (DAT) coding for a truncated DAT protein are in hyperdopaminergic conditions and develop stereotyped behaviors and hyperactivity. Our aim was to test the prior transgenerational modulation of wild and truncated allele as expressed in heterozygous DAT rats: specifically we addressed the possible sequelae due to genotype and gender of the ancestors, with regard to behavioral differences in F1, F2, F3 rats. We studied non-classical DAT heterozygotes based on two specular lines, with putative grand-maternal vs. grand-paternal imprinting. MAT females (F1; offspring of KO male and WT female) mated with a KO male to generate MIX offspring (F2). Specularly, PAT females (F1; offspring of KO female and WT male) mated with a KO male to generate PIX offspring (F2). Similarly to PAT, we obtained MUX (F2; HET offspring of MAT sire and KO dam); we also observed the F3 (MYX: HET offspring of KO male and MUX female, thus with KO maternal grandmother like also for PIX). We studied their circadian locomotor activity and behavior in the elevated-plus-maze (EPM). Locomotor hyper-activity occurs in F1, the opposite occurs in F2, with MYX rats appearing undistinguishable from WT ones. Open-arm preference emerged in PIX and MIX. Only MAT and MYX showed a significant vulnerability for ADHD-like inattentive symptoms (duration of rearing in the EPM; Viggiano et al., 2002). A risk-taking profile is evident in the F2 phenotype while inattentiveness from F1 progeny tends to be transferred to F3. We hypothesize that DAT-related phenotypes result from effective inheritance through pedigree and are dependent on grandparents, suggesting a protective role for gestation of a future PAT dam in hyperdopaminergic uterus. For major features, similar odd (F1, F3) generations appear opposed to even (F2) ones; for minor specific features, the phenotype transfer may affect the progenies with a male but not a female DAT-KO ancestor.