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Abstract
Maternal infection during pregnancy has been associated with increased incidence of schizophrenia in the adult offspring. Mechanistically, this has been partially attributed to neurodevelopmental disruption of the dopamine neurons, as a consequence of exacerbated maternal immunity. In the present study we sought to target hypoferremia, a cytokine-induced reduction of serum non-heme iron, which is common to all types of infections. Adequate iron supply to the fetus is fundamental for the development of the mesencephalic dopamine neurons and disruption of this following maternal infection can affect the offspring's dopamine function. Using a rat model of localized injury induced by turpentine, which triggers the innate immune response and inflammation, we investigated the effects of maternal iron supplementation on the offspring's dopamine function by assessing behavioral responses to acute and repeated administration of the dopamine indirect agonist, amphetamine. In addition we measured protein levels of tyrosine hydroxylase, and tissue levels of dopamine and its metabolites, in ventral tegmental area, susbtantia nigra, nucleus accumbens, dorsal striatum and medial prefrontal cortex. Offspring of turpentine-treated mothers exhibited greater responses to a single amphetamine injection and enhanced behavioral sensitization following repeated exposure to this drug, when compared to control offspring. These behavioral changes were accompanied by increased baseline levels of tyrosine hydroxylase, dopamine and its metabolites, selectively in the nucleus accumbens. Both, the behavioral and neurochemical changes were prevented by maternal iron supplementation. Localized prenatal inflammation induced a deregulation in iron homeostasis, which resulted in fundamental alterations in dopamine function and behavioral alterations in the adult offspring. These changes are characteristic of schizophrenia symptoms in humans.
Highlights
Environmental factors, combined with genetic predisposition, are recognized as key events underlying a number of psychiatric disorders of neurodevelopmental origin, including schizophrenia
In the current study we provided the first evidence, to our knowledge, that localized maternal inflammation during gestation renders adult offspring significantly more sensitive to the locomotor activating effects of a single AMPH injection, and to the behavioral plasticity following repeated exposure to this drug
We demonstrated increased baseline expression of tyrosine hydroxylase (TH) and tissue levels of DA, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), which were specific to the nucleus accumbens (NAcc)
Summary
Environmental factors, combined with genetic predisposition, are recognized as key events underlying a number of psychiatric disorders of neurodevelopmental origin, including schizophrenia. Because a wide variety of viral and bacterial pathogens are implicated [2,17], it is thought that a response common to all forms of infection is involved in the etiology of the disorder [1,18]. One such response is hypoferremia, a cytokinemediated reduction of circulating non-heme iron [19,20,21,22]. Sufficient iron supply is necessary for neurodevelopmental processes; reduction in iron supply at several stages of development results in enduring changes in dopamine (DA) neurotransmission [27,28,29,30] that outlast the iron deficient periods [28,31]
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