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
J Neuroimmune Pharmacol. 2025-04-16; 20(1):
DOI: 10.1007/s11481-025-10186-6
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Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental syndrome typically diagnosed in childhood that may persist into adulthood. Its etiology encompasses both genetic and environmental factors, with genetic studies indicating catecholamine dysfunction and epidemiological evidence emphasizing neuroinflammation as a potential trigger. To investigate the roles of inflammation and development processes in ADHD, we conducted a longitudinal behavioral study using female Swiss mice with a dopamine deficit model. We explored the impact of neonatal dopaminergic lesions, treatment with abscisic acid (ABA)—an anti-inflammatory hormone—and developmental changes by comparing behavioral patterns in juvenile and adult mice. Postmortem analyses assessed neuroinflammation through microglial morphology, NLRP3, cytokine expression, and the excitatory/inhibitory (E/I) ratio in specific brain regions. Neonatal dopaminergic lesions induced hyperactivity and hypersensitivity in juvenile mice that persisted into adulthood. In adults, increased social interaction and memory impairment were observed in lesioned mice. Brain development mitigated impulsivity, while ABA treatment reduced locomotor activity, downregulated pain sensitivity, and influenced social interaction, although it did not completely resolve cognitive deficits in lesioned adult mice. In brain regions such as the anterior cingulate cortex (ACC), posterior insular cortex (pIC), and hippocampus, lesions significantly altered microglial morphology. In the ACC, lesions increased IL-1β and TNFα levels, decreased Arg1 mRNA levels, and disrupted the E/I balance. Importantly, ABA treatment restored microglial morphology, normalized IL-1β and Arg1 expression and upregulated vGAT levels. This study demonstrates that dopamine deficits lead to microglia alterations and E/I imbalance, contributing to ADHD symptoms. While some symptoms improve with brain development, targeting microglial health in specific brain regions emerges as a promising therapeutic approach for managing ADHD.
Graphical Abstract
Effect in adult females of neonatal dopamine depletion and ABA treatment. Brain Neonatal 6-OHDA dopaminergic lesion induces behavioral hyperactivity, impulsivity, hypersensitivity and increased social interaction in P21 and P90 females, and memory impairment in P90. Two-months of ABA treatment improved hyperactivity, anxiety, hypersensitivity, and alterations in social interaction, but not cognitive impairment. In the ACC of young adult mice (P60) dopamine deficiency induced mRNA alteration (as indicated); and E/I imbalance. ABA treatment restored microglia morphology, IL-1β expression, and increased vGAT levels. Black arrows indicate changes at P90 compared to P21 of the same condition; blue arrows indicate changes at P21, compared to SHAM.