Abstract
Epidermal growth factor (EGF) is one of the ErbB receptor ligands implicated in schizophrenia neuropathology as well as in dopaminergic development. Based on the immune inflammatory hypothesis for schizophrenia, neonatal rats are exposed to this cytokine and later develop neurobehavioral abnormality such as prepulse inhibition (PPI) deficit. Here we found that the EGF-treated rats exhibited persistent increases in tyrosine hydroxylase levels and dopamine content in the globus pallidus. Furthermore, pallidal dopamine release was elevated in EGF-treated rats, but normalized by subchronic treatment with risperidone concomitant with amelioration of their PPI deficits. To evaluate pathophysiologic roles of the dopamine abnormality, we administered reserpine bilaterally to the globus pallidus to reduce the local dopamine pool. Reserpine infusion ameliorated PPI deficits of EGF-treated rats without apparent aversive effects on locomotor activity in these rats. We also administered dopamine D1-like and D2-like receptor antagonists (SCH23390 and raclopride) and a D2-like receptor agonist (quinpirole) to the globus pallidus and measured PPI and bar-hang latencies. Raclopride (0.5 and 2.0 µg/site) significantly elevated PPI levels of EGF-treated rats, but SCH23390 (0.5 and 2.0 µg/site) had no effect. The higher dose of raclopride induced catalepsy-like changes in control animals but not in EGF-treated rats. Conversely, local quinpirole administration to EGF-untreated control rats induced PPI deficits and anti-cataleptic behaviors, confirming the pathophysiologic role of the pallidal hyperdopaminergic state. These findings suggest that the pallidal dopaminergic innervation is vulnerable to circulating EGF at perinatal and/or neonatal stages and has strong impact on the D2-like receptor-dependent behavioral deficits relevant to schizophrenia.
Highlights
Epidermal growth factor (EGF) and structurally related EGFlike peptides regulate GABAergic and dopaminergic development [1,2,3,4,5]
Upregulation of dopaminergic markers in the globus pallidus continuing until adulthood At the early postnatal stage of rats, EGF is verified to reach the brain through the immature blood-brain barrier and promote phenotypic development of midbrain dopaminergic neurons, leading to neurobehavioral abnormalities relevant to schizophrenia [26], [31]
These results reveal that EGF exposure to rat pups produces persistent neurotrophic influences on the nigropallidal dopamine neurons and their functions
Summary
Epidermal growth factor (EGF) and structurally related EGFlike peptides (such as neuregulin-1; NRG1) regulate GABAergic and dopaminergic development [1,2,3,4,5]. Changes in the expression levels of EGF, NRG1 and ErbBs are found in postmortem brains and peripheral blood of schizophrenia patients [10,11,12,13]. Among many environmental factors implicated in schizophrenia etiology, maternal viral infection and obstetric complications are suggested to play an important role in regulating vulnerability to schizophrenia [18,19,20,21]. These inflammatory insults often evoke abnormal cytokine signaling and perturb normal brain development [18], [21]. Abnormal ErbB signaling in the prenatal and/or perinatal stage results in the neurobehavioral deficits [26,27,28] and/or dopaminergic abnormalities relevant to schizophrenia [4], the neuropathologic mechanism underlying the individual deficits remains to be clarified
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