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Glutamatergic NMDA (N-methyl D-aspartate) receptors play a critical role in brain development and neurotransmission. Kynurenic acid, an end product of tryptophan degradation along the kynurenine pathway, is an endogenous NMDA receptor antagonist. In the present study, the effects of neurotropic influenza A virus infection on the kynurenine pathway were investigated in mouse brain primary cell cultures and in mouse brain after infection on day 3 of postnatal life. Altered levels of transcripts encoding several key enzymes of the kynurenine pathway were observed in infected neuron and glial cell cultures. In vivo, changes in the levels of such transcripts in brain were observed on postnatal days 7 and 13 but not on day 24. On postnatal day 13, infiltrating T lymphocytes and increased levels of kynurenic acid were observed in the brains of the infected animals. Taken together, the present results indicate that central nervous system infections during early life can activate the entire kynurenine pathway. Such activation is likely to result in the generation of several bioactive metabolites, as supported by our finding of a transient increase of kynurenic acid. In light of its antagonistic actions on the NMDA receptor, kynurenic acid can potentially link infections with glutamatergic signaling in the developing brain., ((c) 2008 Wiley-Liss, Inc.)

In this study, we tested the hypothesis that exposure to a maternal infection during fetal life can lead to the appearance of alterations in the brain later in life. C57BL/6 mice were infected intranasally with influenza A/WSN/33 virus on day 14 of gestation. The levels of transcripts encoding neuroleukin and fibroblast growth factor 5 were significantly elevated in the brains of the virus-exposed offspring at 90 and 280 days of age, but not at earlier time-points. For neuroleukin, this difference could also be observed at the protein level. Thus, a maternal influenza A virus infection can give rise to alterations in gene expression in the brain that become apparent only after a prepubertal latency period.

Abstract: Epidemiological studies suggest that early life infections may contribute to the development of psychiatric disorders characterized by cognitive deficits. Here, we studied the effects of a neonatal influenza A/WSN/33 virus infection on locomotor activity, working memory and emotional behavior in adult mice. In addition to wild type mice, immunodeficient (Tap1 −/−) mice lacking functional CD8+ T cells, were included in the study to model the potential influence of a genetic deficit relating to virus clearance. Three to four months after the infection, infected Tap1 −/− mice, but not wild type mice, exhibited deficits in working memory as well as increased rearing activity and anxiety. In the medial prefrontal cortices of these infected Tap1 −/− mice reduced levels of type III Nrg1 transcripts were observed supporting a role for neuregulin 1 signaling in neuronal circuits involved in working memory. Virus replication, distribution or clearance did not differ between the two genotypes. The lack of CD8+ T cells, however, appeared to contribute to a more pronounced glia response in Tap1 −/− than in wild type mice. Thus, the present study suggest that the risk of developing deficits in cognitive and emotional behavior following a CNS infection during brain development is influenced by genetic variation in genes involved in the immune response. [Copyright &y& Elsevier]