特异性敲除胆碱能神经元上组胺H1受体诱发精神分裂症样阴性症状及其药物靶点的研究

Antipsychotic drugs are mainly aimed at the treatment of the positive symptoms of schizophrenia, with less effect on negative symptoms. The clarification of the pathological mechanism of the negative symptoms and finding new drug targets are difficult but attractive. The applicant has engaged in the study of the role of histamine and its receptors in cerebral disorders. We recently found that selective deletion of H1 receptor (H1R) gene in cholinergic neurons (Hrh1fl/fl; ChATCre) results in schizophrenia-like phenotypes with negative symptoms, including impaired prepulse inhibition (PPI), abnormal social behaviors and anhedonia, but without the positive symptom of increased locomotion. Moreover, neither the deletion of H1R gene in glutamatergic nor in the dopaminergic neurons evokes such schizophrenia-like behaviors, even the dysfunction of glutamatergic or in dopaminergic neurons is closely related to the development of schizophrenia. This project plans to explore the role of H1R in cholinergic neurons in the development of negative symptoms in schizophrenia and the neural circuit related mechanism involving cholinergic projection from basal ganglia to prefrontal cortex, by employing conditional H1R knockout mice, overexpression or knockdown of H1R in the cholinergic projections, optogenetic and pharmacogenetic approaches for modulating the activity of cholinergic neurons, electrophysiology and microdialysis system. This project is aimed to give more evidence to elucidate the pathological mechanism of schizophrenia, especially its negative symptoms and provide new drug targets for precise treatment.

精神分裂症的阴性症状的病理机制非常复杂，缺乏特异性有效治疗药物，阐明其发病机制和寻找新的药物靶点是该领域的研究热点和难点。课题组长期从事组胺及其受体在中枢疾病中的作用研究，近期发现特异性敲除胆碱能神经元上组胺H1受体（H1R）导致了前脉冲抑制缺陷及社交回避、快感缺失等阴性症状，而未出现阳性症状，却发现特异性敲除与精神分裂症发生密切相关的多巴胺或谷氨酸能神经元上H1R并不导致行为改变，提示胆碱能神经元上H1R在阴性症状发生中的重要性。因此，本课题将进一步利用胆碱能神经元上H1R基因敲除小鼠，并利用病毒顺向、逆向追踪及过表达或干扰胆碱能神经上H1R表达，以及利用光遗传学和遗传药理学调控胆碱能神经元活性等方法，结合电生理、微透析等技术，明确胆碱能神经元上H1R在精神分裂症阴性症状发生中的作用及其神经环路机制。本研究将为解析精神分裂症阴性症状的发生机制和精准干预药物靶点的发现提供重要实验依据。

精神分裂症阴性症状是导致患者出现功能障碍的重要原因，目前用于治疗阴性症状的抗精神病药物的疗效并不理想且不特异。本研究中我们发现在精神分裂症患者（同时具有阳性症状和阴性症状）的基底前脑胆碱能神经元中，组胺H1受体（H1R）的mRNA水平显著下降，而精神分裂症患者（仅有阳性症状）并无明显变化。特异性敲除小鼠胆碱能神经元上H1R后导致基底前脑胆碱能神经元向前额叶皮层投射出现障碍，以及导致小鼠感觉门控通道受损、社交功能障碍和快感缺失等精神分裂症样阴性症状相关行为的出现，而并不能引起运动量增加等精神分裂症样阳性症状相关行为。当选择性恢复基底前脑而非纹状体内胆碱能神经元上的H1R或采用化学遗传学特异性激活基底前脑胆碱能神经元后可以逆转敲除小鼠行为的异常。当采用化学遗传学特异性抑制基底前脑胆碱能神经元后小鼠不仅出现精神分裂症样阴性症状相关的行为，同时能够引起对精神分裂症样阳性症状相关行为运动亢进的敏感性升高。此外，选择性在基底前脑胆碱能神经元上过表达H1R后可以逆转MK-801诱导的精神分裂症模型小鼠精神分裂症样阴性症状相关的行为，而对精神分裂症样阳性症状没有影响。然而，特异性敲除多巴胺能或谷氨酸能神经元上H1R并未引起小鼠出现以上行为的改变。因此，本研究表明基底前脑胆碱能神经元上的H1R在精神分裂症阴性症状的发生过程中发挥至关重要的作用，H1R可作为治疗精神分裂症阴性症状的一个新的选择性的靶点。