Reversible Overexpression of Bace1-Cleaved Neuregulin-1 N-Terminal Fragment Induces Schizophrenia-Like Phenotypes in Mice

Background: Neuregulin-1 (Nrg1) is a pleiotropic signaling molecule that regulates neural development, and mutation of Nrg1 is a risk factor for schizophrenia. Cleavage of type I beta 1 Nrg1 isoform by Bace1 releases a secreted N-terminal fragment (Nrg1-ntf(beta)), which can bind to a cognate ErbB receptor to activate the specific signaling cascade. This study aimed to determine whether increased expression of Nrg1 is beneficial for brain development and functions. Methods: We generated transgenic mice overexpressing this fragment under the control of a tetracycline-inducible promoter and examined functional and behavioral changes in mice upon reversible expression of the transgene. Results: Increased expression of full-length Nrg1 in mouse neurons has been previously shown to enhance myelination in the central nervous system. Overexpressing Nrg1-ntf(beta) enhanced the expression of myelin proteins, consistent with the expected activation of the Nrg1 signaling pathway by Nrg1-ntf(beta). Contrary to expectations, overexpressing Nrg1-ntf(beta) transgene caused schizophrenia-like behaviors in transgenic mice, and these abnormal behaviors were reversible if the expression of the Nrg1-ntf(beta) transgene was turned off. Our molecular assay suggests that protein levels of N-methyl-D-aspartate receptors are reduced in this transgenic mouse model, which might underlie the observed social and cognitive behavioral impairments. Conclusions: Our results indicate that overexpressing the secreted form of Nrg1 is sufficient to cause schizophrenia-like behaviors in a mouse model, meaning the effect is independent of the transmembrane and C-terminal domains of Nrg1. Hence, genetic gain-of-function mutations of Nrg1 are also risk factors for schizophrenia.