title: Neuropathologic implication of peripheral neuregulin-1 and EGF signals in dopaminergic dysfunction and behavioral deficits relevant to schizophrenia: their target cells and time window.
abstract: Neuregulin-1 and epidermal growth factor (EGF) are implicated in the pathogenesis of schizophrenia. To test the developmental hypothesis for schizophrenia, we administered these factors to rodent pups, juveniles, and adults and characterized neurobiological and behavioral consequences. These factors were also provided from their transgenes or infused into the adult brain. Here we summarize previous results from these experiments and discuss those from neuropathological aspects. In the neonatal stage but not the juvenile and adult stages, subcutaneously injected factors penetrated the blood-brain barrier and acted on brain neurons, which later resulted in persistent behavioral and dopaminergic impairments associated with schizophrenia. Neonatally EGF-treated animals exhibited persistent hyperdopaminergic abnormalities in the nigro-pallido-striatal system while neuregulin-1 treatment resulted in dopaminergic deficits in the corticolimbic dopamine system. Effects on GABAergic and glutamatergic systems were transient or limited. Even in the adult stage, intracerebral administration and transgenic expression of these factors produced similar but not identical behavioral impairments, although the effects of intracerebral administration were reversible. These findings suggest that dopaminergic development is highly vulnerable to circulating ErbB ligands in the pre- and perinatal stages. Once maldevelopment of the dopaminergic system is established during early development, dopamine-associating behavioral deficits become irreversible and manifest at postpubertal stages.
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Hiroyuki
authors.identifier: 0000-0002-7986-8229
authors.initials: H
authors.lastname: Nawa
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Sotoyama
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takei
authors.affiliation: Department of Molecular Neurobiology, Brain Research Institute, Niigata University, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8585, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Namba
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology; D004815:Epidermal Growth Factor / Q000008:administration & dosage* / Q000378:metabolism; D006801:Humans; D051379:Mice; D020890:Neuregulin-1 / Q000008:administration & dosage* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D020890:Neuregulin-1; D004815:Epidermal Growth Factor; D004298:Dopamine