Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57BL/6J mice

• Published in: Epilepsia (Copenhagen) Vol. 60; no. 4; pp. 626 - 635
• Main Authors: Juda, Michal B., Brooks, Alexandra K., Towers, Albert E., Freund, Gregory G., McCusker, Robert H., Steelman, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.04.2019
• Subjects: 3‐dioxygenase 1; acute seizures; Animal models; Animals; Cardiovirus Infections - complications; Convulsions & seizures; Cytokines; Dioxygenase; Disease Models, Animal; Encephalitis; Encephalitis, Viral - complications; Encephalitis, Viral - enzymology; Epilepsy; Genotypes; Hippocampus; Immunohistochemistry; indoleamine 2; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; infection‐induced seizures; Inflammation; Kynurenic acid; Locomotor activity; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuropathogenesis; Polymerase chain reaction; Quinolinic acid; Ribonucleic acid; RNA; Rodents; Seizures; Seizures - enzymology; Seizures - virology; Theiler's murine encephalomyelitis virus; Theilovirus; Tryptophan; viral encephalitis; epilepsy; indoleamine 2; viral encephalitis; infection-induced seizures; 3-dioxygenase 1; neuropathogenesis; Theiler's murine encephalomyelitis virus; acute seizures
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/epi.14675

Summary Objective Viral encephalitis increases the risk for developing seizures and epilepsy. Indoleamine 2,3‐dioxygenase 1 (Ido1) is induced by inflammatory cytokines and functions to metabolize tryptophan to kynurenine. Kynurenine can be further metabolized to produce kynurenic acid and the N‐methyl‐d‐aspartate receptor agonist quinolinic acid (QuinA). In the present study, we sought to determine the role of Ido1 in promoting seizures in an animal model of viral encephalitis. Methods C57BL/6J and Ido1 knockout mice (Ido1‐KO) were infected with Theiler's murine encephalomyelitis virus (TMEV). Quantitative real‐time polymerase chain reaction was used to evaluate hippocampal expression of proinflammatory cytokines, Ido1, and viral RNA. Body weights and seizure scores were recorded daily. Elevated zero maze was used to assess differences in behavior, and hippocampal pathology was determined by immunohistochemistry. Results Infected C57BL/6J mice up‐regulated proinflammatory cytokines, Ido1, and genes encoding the enzymatic cascade responsible for QuinA production in the kynurenine pathway prior to the onset of seizures. Seizure incidence was elevated in Ido1‐KO compared to C57BL/6J mice. Infection increased locomotor activity in Ido1‐KO compared to C57BL/6J mice. Furthermore, the occurrence of seizures was associated with hyperexcitability. Neither expression of proinflammatory cytokines nor viral RNA was altered as a result of genotype. Immunohistochemical analysis revealed increased hippocampal pathology in Ido1‐KO mice. Significance Our findings suggest that Ido1 deletion promotes seizures and neuropathogenesis during acute TMEV encephalitis.