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Indoleamine 2,3‐dioxygenase 1 deletion promotes Theiler's virus–induced seizures in C57 BL /6J mice
Author(s) -
Juda Michal B.,
Brooks Alexandra K.,
Towers Albert E.,
Freund Gregory G.,
McCusker Robert H.,
Steelman Andrew J.
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.14675
Subject(s) - kynurenine , proinflammatory cytokine , indoleamine 2,3 dioxygenase , kynurenine pathway , quinolinic acid , kindling model , convulsion , hippocampal formation , epilepsy , biology , immunology , viral encephalitis , kynurenic acid , encephalitis , medicine , endocrinology , inflammation , virus , receptor , biochemistry , glutamate receptor , tryptophan , epileptogenesis , amino acid , neuroscience
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 C57 BL /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 C57 BL /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 C57 BL /6J mice. Infection increased locomotor activity in Ido1‐ KO compared to C57 BL /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.