title: Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801.
abstract: Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 μg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner.
authors.forename: T
authors.initials: T
authors.lastname: Kato
authors.forename: Y
authors.initials: Y
authors.lastname: Abe
authors.forename: S
authors.initials: S
authors.lastname: Hirokawa
authors.forename: Y
authors.initials: Y
authors.lastname: Iwakura
authors.forename: M
authors.initials: M
authors.lastname: Mizuno
authors.forename: H
authors.initials: H
authors.lastname: Namba
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Niigata 951-8585, Japan. hnawa@bri.niigata-u.ac.jp.
authors.forename: H
authors.initials: H
authors.lastname: Nawa
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology* / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D020890:Neuregulin-1 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D012559:Schizophrenia / Q000188:drug therapy*; D014018:Tissue Distribution
chemical_list: D020890:Neuregulin-1; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate
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