Phenotypic Characterization of Transgenic Mice Overexpressing Neuregulin-1

Taisuke Kato,Atsushi Kasai,Makoto Mizuno,Liang Fengyi,Hiroyuki Nawa,Sadaaki Maeda,Minesuke Yokoyama,Miwako Ozaki,Norihito Shintani,Thomas Burne

doi:10.1371/journal.pone.0014185

Abstract

BackgroundNeuregulin-1 (NRG1) is one of the susceptibility genes for schizophrenia and implicated in the neurotrophic regulation of GABAergic and dopaminergic neurons, myelination, and NMDA receptor function. Postmortem studies often indicate a pathologic association of increased NRG1 expression or signaling with this illness. However, the psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants.Methodology/Principal FindingsTo assess the behavioral impact of hyper NRG1 signaling, we generated and analyzed two independent mouse transgenic (Tg) lines carrying the transgene of green fluorescent protein (GFP)-tagged type-1 NRG1 cDNA. The promoter of elongation-factor 1α gene drove ubiquitous expression of GFP-tagged NRG1 in the whole brain. As compared to control littermates, both heterozygous NRG1-Tg lines showed increased locomotor activity, a nonsignificant trend toward decreasing prepulse inhibition, and decreased context-dependent fear learning but exhibited normal levels of tone-dependent learning. In addition, social interaction scores in both Tg lines were reduced in an isolation-induced resident-intruder test. There were also phenotypic increases in a GABAergic marker (parvalbumin) as well as in myelination markers (myelin basic protein and 2′,3′-cyclic nucleotide 3′-phosphodiesterase) in their frontal cortex, indicating the authenticity of NRG1 hyper-signaling, although there were marked decreases in tyrosine hydroxylase levels and dopamine content in the hippocampus.ConclusionsThese findings suggest that aberrant hyper-signals of NRG1 also disrupt various cognitive and behavioral processes. Thus, neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation.

Highlights

A genetic association between the neuregulin-1 (NRG1) gene and schizophrenia has been documented in various human populations
Neuropathological implication of hyper NRG1 signaling in psychiatric diseases should be evaluated with further experimentation
As the type-1 NRG1 variant display marked mRNA increase in patients’ postmortem brain and single nucleotide polymorphisms (SNPs) of its corresponding genome locus are implicated in genetic vulnerability to schizophrenia [18], [19], we have established mouse transgenic lines carrying the transgene of mouse type-1 NRG1 cDNA and examined whether NRG1 hypermorphic mice, as opposed to NRG1 hypomorphic mice, are an appropriate animal model for schizophrenia

Summary

Introduction

A genetic association between the neuregulin-1 (NRG1) gene and schizophrenia has been documented in various human populations. The animal and patient studies suggest that decreased NRG1 signals are responsible for the pathophysiology of schizophrenia [14], [15]. The upregulation of the NRG1 protein or its signaling is detected in the brains of schizophrenic patients [20], [21] These patient studies rather suggest a biological link between increased NRG1 signaling and the pathophysiology of schizophrenia. As the type-1 NRG1 variant display marked mRNA increase in patients’ postmortem brain and single nucleotide polymorphisms (SNPs) of its corresponding genome locus are implicated in genetic vulnerability to schizophrenia [18], [19], we have established mouse transgenic lines carrying the transgene of mouse type-1 NRG1 cDNA and examined whether NRG1 hypermorphic mice, as opposed to NRG1 hypomorphic mice, are an appropriate animal model for schizophrenia. The psychobehavioral implication of NRG1 signaling has mainly been investigated using hypomorphic mutant mice for individual NRG1 splice variants

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