41. Longitudinal analysis of ADHD across development in DAT Val559-KI mice
Abstract Background ADHD is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity, often persisting into adulthood. Despite growing recognition, adult ADHD remains under-studied, and its developmental trajectory relative to childhood ADHD is poorly defined. Understanding age-dependent changes in behavior, neurochemistry, and treatment response is critical for refining diagnosis and therapy. The DAT Val559-KI mouse model carries a human-relevant dopamine transporter mutation and reproduces core ADHD features, providing a translational platform for longitudinal investigation of these questions. Aims & Objectives Characterize developmental trajectories of ADHD-like behaviors (inattention, hyperactivity, impulsivity) from childhood to adulthood. Assess age-dependent treatment responses to methylphenidate, identifying efficacy and tolerability across stages. Map neurochemical changes in dopaminergic and noradrenergic systems underlying behavioral and treatment outcomes. Method DAT Val559-KI mice will be studied longitudinally across developmental stages. Locomotor sensitization assays will determine the optimal clinically translated dose of methylphenidate, which will then be applied in subsequent behavioral and molecular experiments. ADHD-relevant behaviors will be quantified using standardized paradigms assessing attention, impulsivity, and activity. Neurochemical analyses will include in vivo electrophysiology, immunohistochemistry, and molecular profiling to evaluate dopaminergic and noradrenergic signaling changes over time. Results We expect to identify age-specific patterns in ADHD-like behaviors and comorbid traits, distinguishing adult from childhood profiles. Methylphenidate efficacy and side-effect profiles are predicted to vary across developmental stages, providing insight into age-tailored therapeutic strategies. Neurochemical analyses are anticipated to reveal dynamic changes in dopamine and norepinephrine signaling that correlate with behavioral outcomes and treatment responses. Discussion & Conclusions This study integrates longitudinal behavioral, pharmacological, and neurochemical analyses in a humanized ADHD mouse model, addressing key gaps in adult ADHD research. Findings will clarify the developmental progression of core symptoms, inform age-specific treatment strategies, and provide mechanistic insight into dopaminergic and noradrenergic contributions to ADHD. Ultimately, this work supports refinement of diagnostic criteria and the development of tailored interventions across the lifespan.