Alterations in the expression of dopamine catabolism genes in DAT-KO rats with induced valproate syndrome

Abstract

BACKGROUND: Autism spectrum disorder and attention deficit hyperactivity disorder are complex disorders of nervous development. Both diseases are diagnosed in childhood and are often comorbital. Rats with a knockout of the dopamine transporter gene (DAT) exhibit symptoms characteristic of attention deficit hyperactivity disorder. Prenatal treatment with valproic acid is used to model autism spectrum disorder. Dysfunction of the dopaminergic system may be one of the causes of attention deficit hyperactivity disorder and autism spectrum disorder. However the neurochemical mechanisms underlying dysfunction of the dopaminergic system and contributing to the pathogenesis of attention deficit hyperactivity disorder require further studies.

AIM: Therefore, the aim of the work was to investigate the expression levels of dopamine catabolism genes in heterozygous rats with a knockout of the DAT encoding gene and induced valproate syndrome.

MATERIALS AND METHODS: The work was performed on 32 rats aged 40 days (adolescence). In total, 4 groups of baby rats were formed in the study: DAT:Salt, DAT:VPA, WT:VPA and WT:Salt, where DAT/WT is the presence or absence of a genetic factor (DAT is a heterozygote for knockout of the SLC6A3 gene, WT is the wild type), VPA/Salt is the presence or absence of a toxic factor (induced valproate syndrome).

RESULTS: The expression of mRNA monoamine oxidase A and monoamine oxidase B in the midbrain was reduced in the groups DAT:Sat, DAT:VPA, WT:VPA compared to the control group WT:Salt. The expression mRNA of catechol-O-methyltransferase mRNA in the midbrain of rats DAT:Salt is significantly higher than in the control group WT:Salt, however, the treatment with valproic acid leads to a decrease in catechol-O-methyltransferase expression in heterozygous rats by knocking out the SLC6A3 gene. No changes in the expression of monoamine oxidase A, monoamine oxidase B, catechol-O-methyltransferase mRNA were observed in the prefrontal cortex and striatum.

CONCLUSIONS: The development of valproate syndrome and/or reduce dopamine reuptake leads to a decrease in the levels of monoamine oxidase A and monoamine oxidase B mRNA in the rat midbrain. Prenatal exposure to valproic acid led to a decrease in the level of catechol-O-methyltransferase mRNA in the midbrain of heterozygous rats by knockout of the DAT gene.

Keywords

autism spectrum disorder / attention deficit hyperactivity disorder / valproic acid / valproic syndrome / dopamine

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