精神分裂症易感基因Neuregulin1过表达损伤树突棘发育的机制

Neuregulin1 (NRG1) is a well-known susceptibility gene of schizophrenia (SCZ), and elevated NRG1 levels have been implicated in SCZ. The ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit SCZ relevant behavioral deficits and hypofunction of synaptic transmission. In our preliminary experiments we found the density of dendritic spines is reduced in the pyramidal neurons in prefrontal cortex and hippocampal CA1 of ctoNrg1 mice. However, the molecular mechanism underlying the impaired dendritic spine development by NRG1 overexpression is still unknown. NRG1 interacts and activates LIMK1, a critical kinase in dendritic spine development. In our study, we will examine the effects of NRG1 overexpression on subcellular distribution and activity of LIMK1 in PSD fraction. Then we further verify if the binding of LIMK1 to NRG1 intracellular domain and activation of LIMK1 by NRG1 overexpression are involved in the dendritic spine development impairment. Finally, we will observe whether manipulation of LIMK1 levels in ctoNrg1 mice can rescue the dendritic spine development impairment by NRG1 overexpression. This study will be helpful for the further understanding of the pathogenic mechanisms of NRG1 in SCZ, and could possibly lead to strategy for the effective treatment of SCZ.

NRG1是公认的精神分裂症(SCZ)易感基因之一，在SCZ中发现其表达增高。前脑兴奋性神经元过表达NRG1的转基因小鼠（ctoNrg1）表现出SCZ相关的行为学缺陷和突触功能异常；我们前期实验发现ctoNrg1小鼠皮层和海马区锥体神经元树突棘密度显著减少，并且mEPSC频率降低，说明过表达NRG1影响树突棘发育，但其中分子机制并不清楚。NRG1结合并激活树突棘发育关键激酶LIMK1，我们推测两者的结合可能参与此过程。本项目将在ctoNrg1小鼠中检测NRG1过表达对LIMK1在PSD中分布及活性的影响，同时在原代神经元中探索两者结合与NRG1过表达引起树突棘发育异常的关系，最后通过在ctoNrg1小鼠内调节LIMK1水平探索NRG1与其结合对树突棘发育的影响以及与SCZ发病之间的关系。本研究将有助于在分子水平上了解过表达NRG1参与SCZ发生的分子机制，并为治疗该病提供新的线索和思路。

神经调节素1（NRG1）及其受体ErbB4编码基因是抑郁症和精神分裂症（SZ）的易感基因，在神经发育和突触可塑性中发挥重要作用。但是，NRG1如何导致SZ并不清楚。SZ病人死后尸检发现前脑组织中NRG1水平升高。本项目拟探索高表达NRG1是否导致树突棘发育和形成异常。我们利用前脑兴奋性神经元过表达NRG1的转基因小鼠（ctoNrg1）为模型，发现ctoNrg1小鼠前额叶皮层和海马锥体神经元树突棘密度和微小兴奋性突触后电流（mEPSCs）频率均降低。高表达NRG1激活LIMK1并增加突触后致密（PSD）中cofilin磷酸化。而抑制LIMK1活性或者抑制NRG1-LIMK1结合可以缓解高表达NRG1引起的树突棘密度降低。这些结果表明脑内维持正常NRG1的水平对于树突棘发育至关重要，同时也为树突棘发育异常引起的相关脑疾病提供了新的病理生理机制。