Galectin-9 increases seizure incidence following acute Theiler’s murine encephalomyelitis virus infection of C57BL/6 mice.

Abstract

The incidence of viral encephalitis is as high as 22/100,000 in children less than 1 year of age. Survivors typically experience neurological sequel, including epilepsy. Infection of C57BL/6 mice with Theiler’s murine encephalomyelitis virus (TMEV) results in the onset of afebrile tonic-clonic seizures beginning at day 3–4 post-infection (p.i.) and is associated with aberrant IL-6 and TNF upregulation as well as apoptosis of CA1 neurons. We previously found that astrocyte galectin-9 (Gal-9) synergized TNF production from microglia following poly(I:C) stimulation. To investigate the role of Gal-9 in the pathogenesis of TMEV-induced seizures we infected control and Lgals9−/− mice and scored each mouse daily for signs of seizures. Following infection, immunohistochemical staining of Lgals9:GFP mouse brains showed a time-dependent increase in hippocampal Gal-9. Gal-9 was maximally expressed prior to the generation of seizures and localized to PECAM1+ endothelial cells, Iba-1+ microglia/macrophages and GFAP+ astrocytes but not NeuN+ neurons. Both RT-qPCR and western blotting techniques confirmed this finding. Furthermore, the incidence, but not severity of seizures was decreased in Lgals9−/− mice compared to controls. Surprisingly, we did not detect significant differences in hippocampal TNF, IL-6 or CCL2 levels, nor blood monocyte and neutrophil populations between genotypes. Together, these data suggests that Gal-9 promotes epileptogenesis during viral encephalitis, but the mechanism remains elusive.