Unraveling Predominantly Inattentive ADHD (ADHD-PI): Insights from Proteomic Analysis of the Striatum of Thyroid Hormone-Responsive Protein (THRSP)–Overexpressing Mice

Abstract

Attention-deficit/hyperactivity disorder, or ADHD, is a neurodevelopmental disorder with poorly understood molecular mechanisms. Recent studies have proposed that gene expression involved in regulating synaptic transmission in the striatum may play a role in ADHD pathogenesis. To explore the molecular basis of ADHD, we utilized proteomic analysis using whole striatal tissues from early adult thyroid hormone-responsive protein-overexpressing (THRSP-OE) mice, which displayed defining characteristics of predominantly inattentive ADHD (ADHD-PI). We focused on the striatal brain region due to its critical role in the regulation of attention, motivation, and reward processing. Moreover, the striatum modulates dopaminergic pathways that are known to be impaired in ADHD. Our analysis revealed an innate overexpression of Snap25 protein in THRSP-OE mice, indicating possible alterations in the SNARE protein complex and potential neurotransmitter dysregulation. Furthermore, a binding affinity study showed reduced dopamine D1 receptor binding concentrations and pronounced low dopamine levels in THRSP-OE mice. Repeated seven-day injections of methylphenidate improved the low dopamine levels, reducing the EEG theta/beta ratio in this animal model. These findings suggest new markers specific to the ADHD-PI presentation and further support the role of Snap25 dysregulation and possible SNARE protein complex alterations in ADHD-PI.

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