精神分裂症的病理机制非常复杂，目前认为谷氨酸、多巴胺能神经功能异常是其主要发病原因，而针对多巴胺的药物存在明显副作用，调控谷氨酸能神经功能是潜在的治疗新方向。申请人预实验发现选择性敲除谷氨酸能神经元上组胺H2受体（H2R）或病毒介导的干扰H2R表达，导致了精神分裂症样表现，包括运动量增加的阳性症状，社交障碍、快感缺失等阴性症状以及前脉冲抑制受损等，提示谷氨酸能神经元上H2R可能在精神分裂症发生中发挥重要作用。本课题将利用谷氨酸能神经元上H2R敲除小鼠（Hrh2fl/fl;CaMKIIa-Cre），及病毒顺向逆向追踪、光遗传学等方法，结合精神分裂症患者脑样本等，明确谷氨酸能神经元上H2R在精神分裂症发生中的作用，及由H2R介导的下丘脑—前额叶皮层（或海马）组胺能神经环路功能障碍、进而导致谷氨酸能神经功能异常的机制。本研究将为阐明精神分裂症的发生机制和发现精准干预的药物靶点提供重要实验依据。

The pathological mechanism of schizophrenia is very complicated. The disorders of glutamatergic and dopaminergic neurotransmission have been proposed as the main causes of schizophrenia, while the drugs against dopamine receptors have obvious side effects. Regulating glutamatergic function may be a potential direction for the treatment. The applicant has engaged in the study of the role of histamine and its receptors in brain disorders. We recently found that selective deletion of H2 receptor (H2R) gene in glutamatergic neurons (Hrh2fl/fl; CaMKIIa-Cre) results in schizophrenia-like phenotypes with positive symptom of hyperlocomotion, negative symptoms of social withdrawal and anhedonia, as well as impaired prepulse inhibition. In addition, it has been reported that the variant of H2R gene is more frequent in the schizophrenic population than controls. This project plans to explore the role of H2R in glutamatergic neurons in the pathogenesis of schizophrenia and the related mechanism involving the blocking of histaminergic projections from hypothalamus to glutamatergic neurons in prefrontal cortex or hippocampus and then the disorder of glutamatergic neurons, by employing the mice with selective knockout of H2R in glutamatergic neurons, antegrade or retrograde trans-monosynaptic viral tracing, optogenetic approaches, and schizophrenia patient brain samples. This project is aimed to give more evidence to elucidate the pathogenesis mechanism of schizophrenia and provide new drug targets for precise treatment.