Institute of Pharmacology & Toxicology, NHC and CAMS Key Laboratory of Medical Neurobiology, College of Pharmaceutical Sciences, School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, P.R. China.
Nat Commun. 2021 Feb 18;12(1):1142. doi: 10.1038/s41467-021-21476-x.
Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H receptor (HR) expression in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of HR gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing HR or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the HR deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.
精神分裂症的阴性症状严重影响患者的功能预后，但阴性症状的发病机制仍不清楚。在这里，我们发现伴有阴性症状的精神分裂症患者基底前脑（BF）胆碱能神经元中的组氨酸 H 受体（HR）表达降低。在小鼠的胆碱能神经元中敲除 HR 基因导致 BF 到前额叶皮质的胆碱能投射功能缺陷，以及感觉运动门控缺陷、社交障碍和快感缺失样行为的形成。这些行为缺陷可以通过重新表达 HR 或通过 BF 中胆碱能神经元的化学遗传激活来挽救。直接化学遗传抑制 BF 胆碱能神经元会产生这种行为缺陷，并增加对过度运动的易感性。我们的研究结果表明，BF 胆碱能神经元中的 HR 缺乏对于感觉运动门控缺陷、社交障碍和快感缺失样行为至关重要。这一发现可能有助于理解精神分裂症阴性症状的遗传和生化基础。
