The roles of indoeamine-2,3-dioxygenase 1 and 2 during TMEV- and kainate-induced ictogenesis
MacDowell Kaswan, Zoe Alexandra
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https://hdl.handle.net/2142/120345
Description
Title
The roles of indoeamine-2,3-dioxygenase 1 and 2 during TMEV- and kainate-induced ictogenesis
Author(s)
MacDowell Kaswan, Zoe Alexandra
Issue Date
2023-04-07
Director of Research (if dissertation) or Advisor (if thesis)
McCusker, Robert H
Doctoral Committee Chair(s)
McCusker, Robert H
Committee Member(s)
Steelman, Andrew J
Christian-Hinman, Catherine A
Rhodes, Justin S
Department of Study
Neuroscience Program
Discipline
Neuroscience
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Ictogenesis
TMEV
kainate
kainic acid
seizure
Ido1
Ido2
neuroimmune
Abstract
Trauma to the brain from infection, injury, or neurotoxic exposure may cause the development of seizures (ictogenesis). These acute seizure events initiate changes that put patients at risk of epilepsy (epileptogenesis), a chronic disease that causes neurodegeneration, cognitive deficits, and significant quality of life impairment. Up to one third of epilepsy patients do not respond to currently available medications, underscoring the urgent need for new avenues of treatment. Neuroinflammation is believed to play a critical role linking initial insult to ictogenesis and subsequent epileptogenesis. We approach this relationship through the lens of indoleamine-2,3-dioxygenase 1 and 2 (Ido1 & Ido2). Both enzymes initiate metabolism of tryptophan to kynurenine, an immune-modulatory compound that may be further metabolized into the neuroprotective metabolite kynurenic acid or the ictogenic metabolite quinolinic acid. Additional non-enzymatic functions have also been described for Ido1 and Ido2. We have previously found that mice with global Ido1 deficiency have increased ictogenesis in the TMEV model of viral encephalitis. Ictogenesis in the TMEV model is inflammation dependent, and expression of Ido1 and Ido2 is induced by inflammatory stimuli. Here, we examine ictogenesis in mice with global Ido2 deficiency and mice with neuron-, astrocyte-, microglia- or myeloid-derived cell-specific Ido1 and Ido2 deficiencies using either TMEV or the chemoconvulsant kainic acid (KA). We find that, in contrast to Ido1KO mice, Ido2KO mice have equivalent TMEV-induced seizure incidence to WT mice, yet have reduced microglial activation. When Ido2, but not Ido1, deficiency is generated in microglia, TMEV-induced ictogenesis is attenuated. However, both Ido1 and Ido2 deficiencies in myeloid-derived cells (i.e. monocytes/macrophages and dendritic cells) reduce TMEV-induced ictogenesis. In vitro infection of microglia and macrophages demonstrates that these cells respond to TMEV via inflammatory stimuli rather than directly to infection itself. In contrast to TMEV, KA treatment causes ictogenesis by direct activation of excitatory kainate-type glutamate receptors. Using this model, we find that Ido2KO, but not Ido1KO, mice have reduced ictogenesis, while several cell-type-specific Ido1 and Ido2 deficiencies increase KA-induced ictogenesis. Overall, our finding demonstrate a role for Ido1 and Ido2 in ictogenesis, although their effect is highly cell-type and etiology-dependent. While further research remains to be done on their mechanisms of action, manipulation of Ido1 and Ido2 may provide a new route for the development of anti-seizure treatment.
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