The functional relevance of neuregulin1-III-mediated bidirectional signaling in prefrontal cortex of mouse

精神分裂症是一种严重的精神障碍，可能会给患者带来毁灭性的后果。编码神经调节蛋白-1(NRG1)及其信号伙伴受体酪氨酸蛋白激酶ErbB-4(ERBB4)的基因是本病的核心候选基因。在成人脑中，表达不同的NRG1蛋白亚型，其中不溶性NRG1-III型是最丰富的亚型。到目前为止，所有NRG1亚型的功能都被认为主要是通过NRG1的EGF样结构域与ERBB4蛋白的相互作用来实现的。因此，非常令人惊讶的是，例如，抑制性突触传递在Nrg1-小鼠突变体中升高，而在ERBB4突变体中受损。这些和其他乍一看相互矛盾的数据支持NRG1的功能可能只是部分通过激活ERBB4依赖的途径来调节的观点。体外数据显示，至少还有一条ERBB4非依赖途径也应该存在。因此，揭示NRG1介导的脑内信号的多样性是我们理解精神分裂症病理生理学的关键一步。因此，根据已发表的数据和我们自己的发现，我们假设NRG1-III双向激活了ERBB4依赖(正向)和非独立(向后)的信号通路，这两个信号通路对大脑的正常功能都是至关重要的。在目前的项目中，专门设计的Nrg1-III转基因小鼠株系将使我们能够直接研究NRG1-III在额叶皮质和海马区明确的突触中介导的“前向和后向信号”的大脑功能，这些突触对于情绪的中枢控制以及精神分裂症的发病机制都是重要的。

Schizophrenia is a serious mental disorder that can have devastating consequences for patients. Genes encoding neuregulin-1 (NRG1) and its signaling partner receptor tyrosine-protein kinase ErbB-4 (ERBB4) belong to the core candidate genes for the disease. In the adult human brain, different NRG1 protein isoforms are expressed, of which the insoluble NRG1-type III is the most abundant isoform. Until now, the function of all NRG1 isoforms is supposed to be mainly mediated by the interaction of the EGF-like domain of NRG1 with the ERBB4 protein. It is therefore very surprising that, for instance, inhibitory synaptic transmission was elevated in Nrg1-mouse mutants, while it was impaired in Erbb4 mutants. These and other at first sight contradictory data support the notion that the function of NRG1 might be only partly mediated by activation of an ERBB4-dependent pathway. At least one additional ERBB4-independent pathway should also exist, as suggested by in-vitro data. Thus, uncovering the diversity of NRG1-mediated signaling in brain arises as a crucial step in our understanding of the pathophysiology of schizophrenia. Based on published data and our own findings, we therefore hypothesize that NRG1-III activates bidirectionally an ERBB4-dependent (forward) and -independent (backward) signaling pathways AND, that both of them are pivotal for the normal function of the brain. In the current project, specifically designed Nrg1-III transgenic mouse lines will allow us to directly investigate the brain functions of NRG1-III- mediated "forward & backward signaling" in defined synapses of prefrontal cortex and hippocampus that are important for the central control of emotion as well as in the pathogenesis of Schizophrenia.