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

• Applicant: Professor Dr. Weiqi Zhang
• Subject Area: Biological Psychiatry ; Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394716173

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.

• DFG Programme: Research Grants