Epidermal growth factor (EGF) and neuregulin-1 are the ErbB receptor ligands that are implicated in schizophrenia neuropathology and neurotrophic regulation of midbrain dopaminergic neurons.mRNA for EGF receptor (ErbB1) was mainly expressed in substantia nigra while that for neuregulin-1 receptor (ErbB4) was more enriched in ventral tegmental area.In agreement, EGF and neuregulin-1 promoted survival and neurite elongation of dopaminergic neurons and/or dopamine uptake in mesencephalic culture.In vivo administration of EGF and neuregulin-1 also up-regulated tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in distinct brain regions.In parallel, there were increases in the density of TH-positive dopaminergic varicosities as well as in local dopamine concentrations.These results confirm that these ErbB ligands contribute to the phenotypic and functional development ofmidbrain dopaminergic neurons.EGF and neuregulin-1 are enriched in human amniotic fluid as well as in blood plasma.To evaluate the effects of prenatal and perinatal ErbB hypersignaling on neurobehavioral development, these neurotrophic factors were subcutaneously administered to rodent neonates as the neurodevelopmental period of rodent perinatal stage that matches the second trimester of human fetus.We found that these factors penetrated the immature blood-brain barrier and reach brain neurons and induced hyperdopaminergic states in the brain.The exposure to EGF and neuregulin-1 later resulted in various behavioral impairments associated with schizophrenia endophenotypes at the post-pubertal stage;acoustic prepulse inhibition (PPI), latent inhibition of learning, social interaction, and methamphetamine hypersensitivity.These findings suggest that dopaminergic development and functions are highly vulnerable to the neurotrophic factors of ErbB ligands (e.g.EGF and neuregulin-1) circulating in the pre-and peri-natal periphery and perturbed in the schizophrenia models established by perinatal exposure to these factors.