过表达神经调节素1导致脑功能障碍的机制研究

Although schizophrenia is a common and disabling mental illness that affects 1% of the population worldwide; its pathophysiological mechanisms remain poorly understood. Neuregulin 1 (Nrg1) is a trophic factor that is critical for neural development and synaptic plasticity. NRG1 and its receptor ErbB4 are schizophrenia susceptibility genes. Exactly how Nrg1 gene variations lead to schizophrenia remains unclear. Recently, elevated Nrg1 levels or signaling have been detected in postmortem brains of schizophrenia patients. In support of Nrg1 overexpression in pathogenesis of schizophrenia, recent studies showed that transgenic mice overexpressing Nrg1 exhibit relevant behavioral deficits. However, little is known about how Nrg1 overexpression leads to schizophrenia-relevant behavioral deficits. In preliminary studies, transgenic mice (ctoNrg1) were generated to overexpress type I Nrg1 in forebrain pyramidal cells. It was found that Nrg1 levels correlated with schizophrenia-relevant behavioral deficits and glutamatergic hypofunction, providing evidence that Nrg1 abnormality impairs brain function. In this proposal, we will study the pathophysiological mechanisms of Nrg1 overexpression from the molecular, cellular and neural circuit levels. We will determine 1) the molecular mechanisms underlying the reduction of glutamate release caused by Nrg1 overexpression; 2) the effects of Nrg1 overexpression on the function of PV-positive GABAergic interneruons in prefrontal cortex; 3) the influence of Nrg1 overexpression on the neuronal synchronization in prefrontal cortex. The results will reveal insight into the pathophysiological mechanisms of schizophrenia.

精神分裂症是一种常见的精神性疾病，其发病率为全球总人口的1%。认知功能障碍是其核心症状之一，但其发病机制尚不清楚。神经调节素1（神调素1）是一类属于营养因子的大家族，在调节神经发育和突触传递及可塑性中发挥重要作用。 神调素1及其受体ErbB4是精神分裂症的易感基因。 神调素1的表达水平或下游信号通路在精神分裂症病人的前额叶皮层和海马是升高的。这提示神调素1的高表达可能在精神分裂症的发病中起一定作用。为研究过表达神调素1的病理生理机制，我们制作了时空特异性的神调素1转基因小鼠，ctoNrg1小鼠。初步研究结果显示ctoNrg1小鼠表现出若干精神分裂症相关的认知功能障碍和谷氨酸释放的减弱。本标书在前期研究结果的基础上，将从分子，细胞和神经网络水平上深入研究过表达神调素1引起认知功能障碍的病理生理机制。研究结果可能为精神分裂症的治疗带来新的思路和靶点。

本项目研究过表达神经调节素1(Nrg1)导致脑功能障碍的机制。我们首先制备了时空特异性Nrg1转基因小鼠-GtoNrg1小鼠：特异性在抑制性中间神经元内过表达Nrg1, 而且这种过表达能够被四环素(Dox)抑制。接下来我们对GtoNrg1小鼠进行了细致的生化、电生理和行为学分析，从分子、细胞和环路水平揭示了在抑制性中间神经元内高表达Nrg1导致社交障碍的神经机制。主要发现如下：NRG1特异性地在抑制性中间神经内高表达可以引起fast-spiking抑制性中间神经元的阈电位升高，兴奋性降低，从而导致锥体神经元的兴奋性增高和theta震荡的抑制。在成年期给予四环素关闭Nrg1的高表达，可以使GtoNrg1小鼠的神经网络和社交行为恢复正常。项目的研究结果对阐明精神分裂症的发病机制具有重要意义。