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

Abstract

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 (PV^SNr) attenuates PV⁺ neuronal activity and induces hyperactivity, impulsivity, and inattention in mice. Moreover, decreased H₂R expression was observed in PV^SNr in patients with ADHD symptoms and dopamine-transporter-deficient mice, whose behavioral phenotypes were alleviated by H₂R agonist treatment. Dysfunction of PV^SNr 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 PV^SNr 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.

Keywords: attention deficit hyperactivity disorder; dopaminergic neurons; histamine; histamine H(2) receptor; intermediate layers of superior colliculus; parvalbumin-positive neuron; substantia nigra pars compacta; substantia nigra pars reticulata.