Analysis of neurotransmitters validates the importance of the dopaminergic system in autism spectrum disorder.

Background: The reasons behind the cardinal symptoms of communication deficits and repetitive, stereotyped behaviors that characterize autism spectrum disorder (ASD) remain unknown. The dopamine (DA) system, which regulates motor activity, goal-directed behaviors, and reward function, is believed to play a crucial role in ASD, although the exact mechanism is still unclear. Investigations have shown an association of the dopamine receptor D4 (DRD4) with various neurobehavioral disorders.
Methods: We analyzed the association between ASD and four DRD4 genetic polymorphisms, 5' flanking 120-bp duplication (rs4646984), rs1800955 in the promoter, exon 1 12 bp duplication (rs4646983), and exon 3 48 bp repeats. We also examined plasma DA and its metabolite levels, DRD4 mRNA expression, and correlations of the studied polymorphisms with these parameters by case-control comparative analyses. The expression of DA transporter (DAT), which is important in regulating the circulating DA level, was also evaluated.
Results: A significantly higher occurrence of rs1800955 "T/TT" was observed in the probands. ASD traits were affected by rs1800955 "T" and the higher repeat alleles of the exon 3 48 bp repeats, rs4646983 and rs4646984. ASD probands exhibited lower DA and norepinephrine levels together with higher homovanillic acid levels than the control subjects. DAT and DRD4 mRNA expression were down-regulated in the probands, especially in the presence of DAT rs3836790 "6R" and rs27072 "CC" and DRD4 rs4646984 higher repeat allele and rs1800955 "T".
Conclusion: This pioneering investigation revealed a positive correlation between genetic variants, hypodopaminergic state, and impairment in socio-emotional and communication reciprocity in Indian subjects with ASD, warranting further in-depth analysis.
(© 2023. Children's Hospital, Zhejiang University School of Medicine.)