Molecular pathology in viral neurophathogenesis of developmental brain disorders

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Developing brains are highly susceptible to cytomegalovirus infection, causing developmental brain disorders. Brain disorders are also induced by reactivation of the virus in immune-compromised patients. In order to certify the hypothesis that latent CMV infection occurs in the brains, neonatal mice were infected with murine CMV (MCMV) and raised for a long time and removed the brains. Reactivation was observed in the brain slice cultures. For further analysis, nestin-promoter-GFP inserted transgenic (Tg) mice (provided Dr.H.Okano, Keio Univ.) were latently infected with MCMV. Immature neural cells cultures in the presence of ganciclovir (GCV), then, neurospheres were isolated. We demonstrated that infective virus is released from the neurospheres by plaque assay. This fact indicates that latent infection may occur in neural stem/progenitor cells. We have showed that neurons tend to become persistent infection and that neuronal expression of the early gene e1-promoter was observed in the transgenic mice. We investigated the effect of MCMV infection on the expression of NMDA rece ptors that are essential for the plasticity of synapses and neuronal excito-toxicity. We showed that expression of NMDA receptors were reduced by MCMV infection, probably relating to establish persistent infection and causing functional disorders. Furthermore, in contrast to neural stem/progenitor cells, we showed that embryonic stem (ES) cells are not susceptible to MCMV infection but acquired the susceptibility during the glial differentiation.