Microglia-specific Ido2 deficiency attenuates ictogenesis in the TMEV model of viral encephalitis

Abstract

Viral encephalitis is a serious condition that causes acute neuroinflammation, neurodegeneration, cognitive deficits and behavioral changes, while putting patients at risk of developing seizures (ictogenesis) and post-encephalitis epilepsy. Intracerebral injection of C57BL/6 mice with Theiler’s murine encephalomyelitis virus (TMEV) is a model of viral encephalitis that causes behavioral seizures along with substantial neurodegeneration and neuroinflammation. This model is considered a benchmark preclinical paradigm for the investigation of hippocampal-dependent viral ictogenesis and temporal lobe epilepsy. Inflammation-induced indolealine2,3-deoxygenase (Ido) 1 and 2 initiate the conversion of tryptophan into kynurenine, which is subsequently converted into downstream neuroactive metabolites with the ability to modify behavioral seizures. Ido1 and Ido2 have also been shown to have non-redundant roles in modulating several inflammatory diseases. We have previously shown that Ido1 deficiency increases TMEV-induced behavioral seizure incidence using wild type (WT, C57BL/6J) mice. Here, we extend those findings to Ido2 deficiencies. We find that Ido2^KO (knockout) mice have equivalent TMEV-induced behavioral seizure incidence and hippocampal gene expression relative to wild type WT mice. However, while TMEV infection causes an increase in Iba1⁺ staining throughout the hippocampus (indicating microglial activation) this effect is ameliorated in Ido2^KO mice. Microglia, the resident innate immune cells of the brain, are critical for TMEV clearance but may also contribute to ictogenesis. Therefore, based on Ido2-dependent differences in microglia activation, we examined TMEV-induced ictogenesis in mice with microglial-specific Ido1 and Ido2 deficiencies. We found that microglial Ido2, but not Ido1, deficiency reduced ictogenesis but caused minimal changes in hippocampal gene expression. In vitro treatments revealed that microglia respond to TMEV infection via inflammatory signals rather than directly to viral infection itself. In sum, we demonstrate that Ido2 plays a key role in microglial response to TMEV and that, when the effects of Ido2 deficiency are limited to microglia, Ido2 deficiency is protective against ictogenesis.