Cytomegalovirus infection in newborn mice alters cerebellar development by lengthening G1/S phases of cerebellar granule cell precursors during postnatal cerebellar development

Human cytomegalovirus (HCMV) infection of the developing central nervous system (CNS) in infants infected in utero can lead to a variety of neurodevelopmental disorders. Although the link between HCMV infection and neurodevelopmental deficits is widely recognized, underlying mechanisms leading to altered neurodevelopment remain poorly understood. We have previously described a murine model of congenital HCMV infection in which murine CMV (MCMV) spreads hematogenously and establishes a focal infection in the brain of newborn mice. Infection results in the disruption of cerebellar cortical development characterized by reduced cerebellar size, but paradoxically, an increase in the number of cerebellar granule cell precursors (GCPs) in the external granular layer (EGL) of the cerebellar cortex. This increased number of GCPs in the EGL is associated with abnormal cell cycle progression and decreased GCP migration from EGL and IGL. In the current study, we demonstrated that MCMV infection led to prolonged G1- and S-phases of the GCP cell cycle and increased cell cycle exit. Treatment with TNFα neutralizing antibody partially normalized the cell cycle progression of GCPs. Collectively, our results argue that inflammation can alter GCP proliferation and lead to premature exit from the cell cycle resulting in reduced cerebellar size in MCMV-infected mice. These findings provide insight into mechanisms of altered brain development of fetuses infected with HCMV and possibly, other infectious agents that induce inflammation during neurodevelopment.