Deficiency of histamine H2 receptors in parvalbumin-positive neurons leads to hyperactivity, impulsivity, and impaired attention

Attention deficit hyperactivity disorder (ADHD), affecting 4% of the population, is characterized by inattention, hyperactivity, and impulsivity; however, its neurophysiological mechanisms remain unclear. Here, we discovered that deficiency of histamine H2 receptor (H2R) in parvalbumin-positive neurons in substantia nigra pars recticulata (PVSNr) attenuates PV+ neuronal activity and induces hyperactivity, impulsivity, and inattention in mice. Moreover, decreased H2R expression was observed in PVSNr in patients with ADHD symptoms and dopamine-transporter-deficient mice, whose behavioral phenotypes were alleviated by H2R agonist treatment. Dysfunction of PVSNr efferents to the substantia nigra pars compacta dopaminergic neurons and superior colliculus differently contributes to H2R-deficiency-induced behavioral disorders. Collectively, our results demonstrate that H2R deficiency in PV+ neurons contributes to hyperactivity, impulsivity, and inattention by dampening PVSNr activity and involving different efferents in mice. It may enhance understanding of the molecular and circuit-level basis of ADHD and afford new potential therapeutic targets for ADHD-like psychiatric diseases. •H2 receptor deficiency in PV+ neurons induces hyperactivity, impulsivity, and inattention•H2 receptor deficiency dampens PVSNr neuronal activity•H2 receptor in PVSNr regulates attention, impulsivity, and motion via distinct efferents•The H2 receptor agonist can alleviate behavioral abnormalities in an ADHD mice model ADHD is a common behavioral disorder with elusive mechanisms. An et al. identify the cell type, brain region, and neural circuits through which the H2 receptor contributes to hyperactivity, impulsivity, and inattention, enhancing understanding of the molecular and circuit-level basis of ADHD and offering a potential precise therapeutic target.