敲除多巴胺及其受体D2阳性神经元中ErbB4引起精神分裂症表型的机制

Neuregulin 1 (NRG1) and its receptor ErbB4 are susceptibility genes of schizophrenia (SCZ), hypofunction of this pathway results in SCZ phenotypes, however, it is still unclear whether dopamine (DA) transmission is involved in leading SCZ phenotypes by hypofunction of this pathway. Our preliminary results showed specific knockout ErbB4 in DA neurons increased DA release and impaired fear memory, and in dopamine receptor D2 (DRD2) positive neurons also impaired fear memory, indicated ErbB4 knockout could lead SCZ phenotypes through DA transmission. To clarify the influences and the mechanisms that NRG1/ErbB4 signaling regulates DA transmission, we will confirm the spectrum of SCZ phenotypes of the mice that knockout ErbB4 in DA or DRD2 positive neurons, clarify the related ErbB4 downstream pathways, illustrate ErbB4 knockout effect on the excitability and neurotransmitter release of DA and DRD2 positive neurons and investigate its mechanisms, and probe the feasibility to rescue the fear memory deficit of ErbB4 knockout mice in both DA and DRD2 positive neurons. Our study will shed light on understanding the pathology of SCZ phenotypes caused by NRG1/ErbB4 hypofunction, and help to develop novel ideas and therapeutic approaches for clinic treatment.

神经调节素1（NRG1）及其受体ErbB4是精神分裂症（SCZ）的易感基因，该信号通路减退可导致SCZ表型，但多巴胺（DA）能递质传递改变是否参与该信号通路减退引起SCZ表型尚不清楚。我们初步结果显示在DA神经元中敲除ErbB4可使DA释放增加，DA或其受体D2（DRD2）阳性神经元中ErbB4敲除小鼠均有恐惧记忆缺陷。上述结果提示ErbB4敲除可以通过影响DA递质传递导致SCZ表型。为进一步明确ErbB4调节DA递质传递的具体机制，本研究将分析DA以及DRD2阳性神经元敲除ErbB4小鼠的SCZ表型，明确ErbB4相关下游通路，阐明ErbB4敲除对神经元兴奋性以及递质释放的影响及其机制，并探讨挽救DA和DRD2阳性神经元中同时敲除ErbB4的小鼠恐惧记忆表型的可能性。本研究将有助于理解NRG1/ErbB4功能减退引起SCZ的发病机制，并为临床治疗SCZ提供新的思路和靶点。

神经调节素1（NRG1）及其受体ErbB4是精神分裂症（SCZ）的易感基因，该信号通路异常将引起SCZ相关表型。适度运动能够缓解SCZ相关表型，其机理是否与NRG1/ErbB4信号通路有关尚有待进一步研究。在本研究中，我们发现适度运动可以促进海马齿状回中ErbB4的表达，从而通过增强parvalbumin（PV）阳性GABA能神经元的活性促进神经发生，抑制精神分裂症相关表型。此外我们还发现中药黄芪甲苷也通过相似途径抑制精神分裂症相关表型，从而为临床治疗该疾病提供理论依据。更为有趣的是，通过该项目我们还发现了另一个与ErbB4相互作用的精神分裂症易感基因GM527，其机理可能通过多巴胺受体阳性神经元引起精神分裂症相关表型，从而为进一步研究精神分裂症的机理和治疗方法提供了新的靶点。