Deficiency of histamine H 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 H receptor (HR) in parvalbumin-positive neurons in substantia nigra pars recticulata (PV) attenuates PV neuronal activity and induces hyperactivity, impulsivity, and inattention in mice. Moreover, decreased HR expression was observed in PV in patients with ADHD symptoms and dopamine-transporter-deficient mice, whose behavioral phenotypes were alleviated by HR agonist treatment. Dysfunction of PV efferents to the substantia nigra pars compacta dopaminergic neurons and superior colliculus differently contributes to HR-deficiency-induced behavioral disorders. Collectively, our results demonstrate that HR deficiency in PV neurons contributes to hyperactivity, impulsivity, and inattention by dampening PV 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.