Elsevier

Biological Psychiatry

Volume 76, Issue 2, 15 July 2014, Pages 120-127
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.09.026Get rights and content

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 β1 Nrg1 isoform by Bace1 releases a secreted N-terminal fragment (Nrg1-ntfβ), 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-ntfβ enhanced the expression of myelin proteins, consistent with the expected activation of the Nrg1 signaling pathway by Nrg1-ntfβ. Contrary to expectations, overexpressing Nrg1-ntfβ transgene caused schizophrenia-like behaviors in transgenic mice, and these abnormal behaviors were reversible if the expression of the Nrg1-ntfβ 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.

Section snippets

Generation of Human N1β Transgenic Mice

The BACE1-cleaved N-terminal fragment of human NRG1 β1a (N1β) was subcloned into the BamHI and NotI sites of pTRE2hyg vector (Clontech Laboratories, Mountain View, California). A linearized NheI fragment containing the transgene was used for transgenic mouse production. Five TRE-N1β founders in the C57BL/6-CBA(J) background were identified by polymerase chain reaction with primers (forward CATCGTGGAATCAAACGAGA; reverse TTTGCCCCCTCCATATAACA) and further confirmed by Southern blotting. The Tg-N1β

Generation of Transgenic Mice Expressing Nrg1-ntfβ Transgene

We have previously mapped Bace1 cleavage of Nrg1 to the site between amino acids F237 and M238, which is located 10 amino acids upstream of the transmembrane domain of the Nrg1 β1 isoform (7). This has been confirmed in separate studies 9, 14. To generate transgenic mice overexpressing Bace1-cleaved Nrg1 β1 isoform (Nrg1-ntfβ), we subcloned the corresponding fragment into a vector under the control of an inducible tetracycline responsive element (Figure 1A). The assembled construct was then

Discussion

The Nrg1 is an indispensable signaling molecule for the control of neural development and neuronal functions 35, 36, 37. The Nrg1 initiates its signaling activity by binding to its cognate tyrosine kinase receptor, consisting of an ErbB2/ErbB3 heterodimer or an ErbB4 homodimer, which induces a cascade of signaling events including phosphorylation of the downstream molecules Akt and Erk. Membrane-bound pro-Nrg1 protein seems to be inactive, because the EGF-like domain within the N-terminal

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