Abstract
BackgroundThere is mounting evidence for a neurodevelopmental basis for disorders such as autism and schizophrenia, in which prenatal or early postnatal events may influence brain development and predispose the young to develop these and related disorders. We have now investigated the effect of a prenatal immune challenge on brain development in the offspring. Pregnant rats were treated with the double-stranded RNA polyinosinic:polycytidylic acid (poly(I:C); 10 mg/kg) which mimics immune activation occurring after activation of Toll-like receptors-3 (TLR3) by viral infection. Injections were made in late gestation (embryonic days E14, E16 and E18), after which parturition proceeded naturally and the young were allowed to develop up to the time of weaning at postnatal day 21 (P21). The brains of these animals were then removed to assess the expression of 13 different neurodevelopmental molecules by immunoblotting.ResultsMeasurement of cytokine levels in the maternal blood 5 hours after an injection of poly(I:C) showed significantly increased levels of monocyte chemoattractant protein-1 (MCP-1), confirming immune activation. In the P21 offspring, significant changes were detected in the expression of GluN1 subunits of NMDA receptors, with no difference in GluN2A or GluN2B subunits or the postsynaptic density protein PSD-95 and no change in the levels of the related small GTPases RhoA or RhoB, or the NMDA receptor modulator EphA4. Among presynaptic molecules, a significant increase in Vesicle Associated Membrane Protein-1 (VAMP-1; synaptobrevin) was seen, with no change in synaptophysin or synaptotagmin. Proliferating Cell Nuclear Antigen (PCNA), as well as the neurogenesis marker doublecortin were unchanged, although Sox-2 levels were increased, suggesting possible changes in the rate of new cell differentiation.ConclusionsThe results reveal the induction by prenatal poly(I:C) of selective molecular changes in the brains of P21 offspring, affecting primarily molecules associated with neuronal development and synaptic transmission. These changes may contribute to the behavioural abnormalities that have been reported in adult animals after exposure to poly(I:C) and which resemble symptoms seen in schizophrenia and related disorders.
Highlights
There is mounting evidence for a neurodevelopmental basis for disorders such as autism and schizophrenia, in which prenatal or early postnatal events may influence brain development and predispose the young to develop these and related disorders
This is consistent with previous work showing that an increase in tumour necrosis factor-α (TNF-α) reaches a peak around 2-3 h following poly(I:C) administration in vivo [12,13], while others have reported no change in IL-1β levels after injection of poly(I:C) [14,15]
It should be emphasised that these comments apply to maternal blood since brains from the embryos were not examined in this study and we cannot exclude the possibility that changes occurred in the foetal brain that are not mirrored in the maternal circulation
Summary
There is mounting evidence for a neurodevelopmental basis for disorders such as autism and schizophrenia, in which prenatal or early postnatal events may influence brain development and predispose the young to develop these and related disorders. Represent an important contributor to the emergence of neurodevelopmental disorders including schizophrenia, autism spectrum disorders and depression [3,4,5] This hypothesis is supported by experimental evidence from rodent models that infection during gestation may lead to behavioural changes in the offspring which may not be apparent until adulthood. Many infections of pregnancy are caused by viruses, the effects of which can be simulated by the synthetic viral coat-mimetic poly-[inosinic acid:cytidylic acid], (poly(I:C)) This double-stranded RNA molecule activates Toll-Like Receptor-3 (TLR-3) on dendritic cells, macrophages and B cells, leading to activation of the immune system. The effects of poly(I:C) include inducing the expression of interferon-γ (IFN-γ) and other major inflammatory mediators such as interleukin-1β (IL-1β), IL-6 and tumour necrosis factor-α (TNF-α), as well as leucocyte chemoattractants such as monocyte chemotactic protein-1 (MCP-1) [11], reproducing many features of a full infective immune response
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