Motor Transitions’ Peculiarity of Heterozygous DAT Rats When Offspring of an Unconventional KOxWT Mating

• Published in: Neuroscience Vol. 433; pp. 108 - 120
• Main Authors: Carbone, Cristiana, Brancato, Anna, Adinolfi, Annalisa, Lo Russo, Sara Lucia Maria, Alleva, Enrico, Cannizzaro, Carla, Adriani, Walter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.05.2020
• Subjects: Animals; Brain - metabolism; DAT heterozygous rat; depressive-like phenotype; Dopamine; Dopamine Plasma Membrane Transport Proteins - genetics; Dopamine Plasma Membrane Transport Proteins - metabolism; Female; Heterozygote; histone-deacetylase; Male; Methylphenidate - pharmacology; nucleus accumbens; parent-of-origin effect; Rats; Ventral Striatum - metabolism; histone-deacetylase; ADHD; HDACs; DAT; POE; depressive-like phenotype; parent-of-origin effect; SLC6; nucleus accumbens; DAT heterozygous rat
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2020.03.005

•DAT hypo-functional (heterozygous, HET) rat dams are known to display less maternal care.•We compared MAT-HET (KO-male × WT-female) to MIX-HET (heterozygous parents) rats.•MAT-HETs had more transitions between escape (diving) and despair (floating) on Porsolt.•When comparing to MIX-HETs, MAT-HETs displayed increased DAT in the dorsal-striatum.•MAT-HETs could help exploring parent-of-origin mechanisms in peculiar bipolar phenotypes. Causal factors of psychiatric diseases are unclear, due to gene × environment interactions. Evaluation of consequences, after a dopamine-transporter (DAT) gene knock-out (DAT-KO), has enhanced our understanding into the pathological dynamics of several brain disorders, such as Attention-Deficit/Hyperactivity and Bipolar-Affective disorders. Recently, our attention has shifted to DAT hypo-functional (heterozygous, HET) rodents: HET dams display less maternal care and HET females display marked hypo-locomotion if cared by HET dams (Mariano et al., 2019). We assessed phenotypes 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-HET subjects had significantly longer rhythms of daily locomotor activity than MIX-HET and WT-control subjects. Furthermore, acute methylphenidate (MPH: 0, 1, 2 mg/kg) revealed elevated threshold for locomotor 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 behavioral despair (floating). When comparing both MAT- and MIX-HET to WT-control rats, decreased levels of DAT and HDAC4 were evident in the ventral-striatum; moreover, with respect to MIX-HET subjects, MAT-HET ones displayed increased DAT density in dorsal-striatum. MAT-HET rats displayed region-specific changes in DAT expression, compared to “classical” MIX-HET subjects: greater DAT availability may elevate threshold for dopamine action. Further behavioral and epigenetic characterizations of MAT-HETs, together with deeper characterization of maternal roles, could help to explore parent-of-origin mechanisms for such a peculiar phenotype.