Truncated dopamine transporter's epigenetics: Heterozigosity of the grandmother rat temperates the vulnerable phenotype in second-generation offspring.

Abstract

Behavioral phenotype differs among epigenotypes of dopamine-transporter heterozygous (DAT-HET) rats. Epigenetic regulations act through transgenerational effects, referring to phenotypic variations emerging at second or third generation. To investigate transgenerational influences exerted by maternal grandmothers, we developed breeding schemes where only the genotype of maternal grandmothers varied. HET females, to serve as MAT vs. MIX mothers, were generated, respectively, from WT × KO = MAT and MAT × KO = MIX breeding, with KO males acting as grandfather. The HET experimental groups, generated from either MAT or MIX mothers, were called MIX-by-MAT and MIX2 (male-fathers KO; asset-M: wild/healthy-allele from dam) or SOT and SIX (male-fathers WT; asset-P: mutated-allele from dam). Thus, sequelae of first encounter between wild/healthy and mutated DAT alleles (in maternal-lineage) were compared at first- (MAT-dam, WT-grandmother) vs. at second- (MIX-dam, HET-grandmother) generation. We characterized, within these epigenotypes, (1) circadian home-cage activity and (2) preference for social stimuli. Marked alterations of circadian activity appeared in MIX-by-MAT HETs, offspring of MAT-dams, compared with MIX2 HET (offspring of MIX-dams); The latter, in turn, were undistinguishable from WT-controls. A clear-cut social preference by WT rats was expressed towards SIX compared with SOT stimulus rats, confirming that the latter elicited reduced social motivations. In conclusion, significant epigenetic modulations took place in DAT-HET rats, as a function of maternal grandmother's genotype.