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

Dadao An; Yi You; Qianyi Ma; Zhengyi Xu; Zonghan Liu; Ruichu Liao; Han Chen; Yiquan Wang; Yi Wang; Haibin Dai; Haohong Li; Lei Jiang; Zhong Chen; Weiwei Hu

doi:10.1016/j.neuron.2024.12.002

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

Neuron. 2025 Jan 6:S0896-6273(24)00880-8. doi: 10.1016/j.neuron.2024.12.002. Online ahead of print.

Authors

Dadao An¹, Yi You², Qianyi Ma², Zhengyi Xu³, Zonghan Liu², Ruichu Liao², Han Chen², Yiquan Wang⁴, Yi Wang³, Haibin Dai², Haohong Li⁵, Lei Jiang², Zhong Chen⁶, Weiwei Hu⁷

Affiliations

¹ Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310053, China.
² Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China.
³ Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310053, China.
⁴ Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University, Hangzhou 310013, China.
⁵ The MOE Frontier Research Center of Brain and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China.
⁶ Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: chenzhong@zju.edu.cn.
⁷ Department of Pharmacology and Department of Pharmacy of the Second Affiliated Hospital, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: huww@zju.edu.cn.

PMID: 39788124
DOI: 10.1016/j.neuron.2024.12.002

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.