Abscisic Acid rescues behavior in adult female mice in Attention Deficit Disorder with Hyperactivity model of dopamine depletion by regulating microglia and increasing Vesicular GABA Transporter expression

Background: Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome influenced by both genetic and environmental factors. While genetic studies have highlighted catecholamine dysfunction, emerging epidemiological evidence suggest neuroinflammation as a significant trigger. However, understanding the relative contributions of these alterations to ADHD symptomatology remains elusive. Method: This study employed 93 female Swiss mice of the ADHD dopamine deficit model. Dopaminergic lesions were induced via 6-hydroxidopamine (6-OHDA) injection on postnatal day 5. The impact of these lesions during development was examined by comparing young and adult mice (at postnatal day 21 and 90, respectively). We sought to mitigate adult symptoms through abscisic acid (ABA) administration during two-months. Postmortem analyses encompassed the evaluation of neuroinflammation (microglia morphology, NLRP3 inflammasome activation, cytokine expression) and excitatory/inhibitory (E/I) ratio in specific brain regions. Results: Neonatal dopaminergic lesions elicited hyperactivity, impulsivity, increased social interaction in both young and adult females and lesion induce impaired memory in adults. ABA exposure significantly ameliorated hyperactivity, impulsivity, anxiety, hypersensitivity, and social interaction alterations, but not cognitive impairment in adults. In the anterior cingulate cortex (ACC) of young mice dopamine-deficit induced microglia morphology alterations, elevated IL-1β and TNFa expression and reduced Arg1 mRNA levels, along with E/I imbalance. ABA intervention restored microglia morphology, IL-1β expression and enhanced vGAT levels. Conclusions: This study strongly suggest that dopamine deficit induced alteration of microglia and E/I ratio underling distinct ADHD symptoms. Reinstating healthy microglia by anti-inflammatory agents in specific areas emerges as a promising strategy for managing ADHD.