Transient exposure of neonatal mice to neuregulin-1 results in hyperdopaminergic states in adulthood: implication in neurodevelopmental hypothesis for schizophrenia.
Neuregulin-1 (NRG1) is implicated in the etiology or pathology of schizophrenia, although its biological roles in this illness are not fully understood. Human midbrain dopaminergic neurons highly express NRG1 receptors (ErbB4). To test its neuropathological role in the neurodevelopmental hypothesis of schizophrenia, we administered type-1 NRG1 protein to neonatal mice and evaluated the immediate and subsequent effects on dopaminergic neurons and their associated behaviors. Peripheral NRG1 administration activated midbrain ErbB4 and elevated the expression, phosphorylation and enzyme activity of tyrosine hydroxylase (TH), which ultimately increased dopamine levels. The hyperdopaminergic state was sustained in the medial prefrontal cortex after puberty. There were marked increases in dopaminergic terminals and TH levels. In agreement, higher amounts of dopamine were released from this brain region of NRG1-treated mice following high potassium stimulation. Furthermore, NRG1-treated mice exhibited behavioral impairments in prepulse inhibition, latent inhibition, social behaviors and hypersensitivity to methamphetamine. However, there were no gross abnormalities in brain structures or other phenotypic features of neurons and glial cells. Collectively, our findings provide novel insights into neurotrophic contribution of NRG1 to dopaminergic maldevelopment and schizophrenia pathogenesis.
Kato
T
T
Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan.
Abe
Y
Y
Sotoyama
H
H
Kakita
A
A
Kominami
R
R
Hirokawa
S
S
Ozaki
M
M
Takahashi
H
H
Nawa
H
H
D000161:Acoustic Stimulation; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D019921:Biotinylation; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006309:Hearing / Q000187:drug effects; D047468:Immunoprecipitation; D007980:Levodopa / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D017551:Microdialysis / Q000379:methods; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D018967:Risperidone / Q000494:pharmacology; D012919:Social Behavior; D018709:Statistics, Nonparametric; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018492:Dopamine Antagonists; D020890:Neuregulin-1; D016760:Proto-Oncogene Proteins c-fos; D008694:Methamphetamine; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D018967:Risperidone; D011188:Potassium; D004298:Dopamine