Downregulation of integrin α3 in ADHD mirrored in mutant mouse model by dopamine-dependent hippocampal AMPAR...

Integrin α3 is critical for proper neuron-glia cell adhesion and dendrite development, implicated in various neurodevelopmental disorders. In this study, mice deficient in integrin α3 (NEX-Itga3^-/- mice) exhibit behavioral anomalies that mirror Attention Deficit Hyperactivity Disorder (ADHD), including increased mobility, impulsive disinhibition and impaired working memory. The mutant mice exhibit a reduced hippocampal volume and decreased α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) surface distribution in the hippocampus. Utilizing two-pimaging combined with whole-cell recordings, diminished AMPAR function and increased prevalence of silent synapses were observed in the NEX-Itga3^-/- mice. Systemic treatment with methylphenidate (MPH) and intra-hippocampal administration of the dopamine D1 receptor agonist SKF81297 improved ADHD-like behaviors, associated with enhanced dopamine D1 receptor activity and increased insertion of AMPARs in the hippocampus. Our analysis of the ABCD database uncovered a significant positive correlation between reduced integrin α3 expression and the prevalence of ADHD in adolescent humans. By identifying hippocampal AMPAR regulation as a key pathway through which ITGA3 influences ADHD-related phenotypes, this study uncovers a previously underappreciated hippocampal mechanism in ADHD and suggests new therapeutic strategies targeting synaptic modulation and hippocampal circuits.