The drug development and identification of risk factor through animal model of schizophrenia

近年来的分子遗传学研究表明，编码神经调节蛋白-1（NRG-1）的基因可能是精神分裂症的易感基因之一。新生大鼠腹侧海马（NVH）损伤被认为是精神分裂症的一个假定模型，具有对应激和神经兴奋剂反应的特征性青春期后改变。在本研究中，我们研究了NRG-1，erbB 4受体的水平和受体的信号转导，在青春期后的NVH病变大鼠的前额叶皮层（PFC），通过免疫组织化学和免疫印迹分析。定量分析显示，青春期后NVH损伤的动物显示PFC中NRG-1和erbB 4磷酸化水平显着降低，与假手术对照组相比。将NRG-1微量注射到NVH损伤大鼠的PFC中可减轻前脉冲抑制（PPI）的缺陷。结果提示，PFC内erbB_4信号异常可能在NVH大鼠PPI受损中起重要作用。NRG-1/erbB 4信号通路可能成为精神分裂症治疗的新靶点。

Recent molecular genetics studies in human have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Neonatal ventral hippocampal (NVH) lesions in rats have been considered as a putative model of schizophrenia with characteristic post-pubertal alteration in response to stress and neuloleptics. In this study, we examined the levels of NRG-1, erbB4 receptors and the receptor's signaling in prefrontal cortex (PFC) of post-pubertal rats with NVH lesions, by using immunohistochemical and immunoblotting analyses. Quantitative analyses revealed that post-pubertal NVH-lesioned animals display significantly decreased levels of NRG-1 and erbB4 phosphorylation in PFC compared to sham controls. Microinjection of NRG-1 to PFC of NVH lesioned rats attenuated deficits in prepulse inhibition (PPI). These results that abnormal of erbB4 signaling in the PFC may play important roles in PPI deficits in NVH lesioned rats. NRG-1/erbB4 signaling may be novel therapeutic targets for schizophrenia.