Ido1 and Ido2 deficiencies attenuate kainic acid-induced ictogenesis

• First evidence that both Ido1 and Ido2 play key roles during kainite-induced seizures. • The data indicate a non-enzymatic role for hippocampal Ido1 and Ido2 in ictogenesis. • Neither Ido1 nor Ido2 control basal or kainite-induced inflammatory status. Insults to the brain in the form of injury, infection and exposure to seizurogenic chemicals can induce seizures (ictogenesis). Seizure episodes during any of these events is one of the biggest risk factors for the development of treatment-resistant epilepsy, making the acute ictogenic period a critical time for intervention. Indoleamine-2,3-dioxygenases (Ido1 & Ido2) modulate systemic and central neuroprotective and inflammatory responses through both enzymatic and non-enzymatic mechanisms. We have previously found that Ido1 −/− (knockout) mice have increased seizure incidence following viral encephalitis suggesting a protective role of Ido1 during this inflammatory model of ictogenesis. Here, we assessed ictogenesis with Ido1 −/− and Ido2 −/− mice using intraperitoneal injections of the chemoconvulsant kainic acid (KA). We found that Ido1 −/− and Ido2 −/− mice have reduced seizure incidence after systemic KA treatment compared to WT controls. However, neither Ido1 nor Ido2 expression was induced by KA and indices of inflammation (hippocampal cytokine expression) did not vary across genotypes. Nevertheless, Ido2 −/− mice were also protected from the KA-induced hyperlocomotion observed with WT mice. Because Ido1 and Ido2 are expressed by multiple cell types within the brain, we evaluated KA-induced ictogenesis using mice with cell-type-specific Ido1 and Ido2 deficiencies. Ido1 or Ido2 deficiency in neurons, astrocytes and myeloid-derived cells all increase ictogenesis, while only a deficiency of microglial Ido2 (not Ido1) had this enhancing effect. Thus, the results of cell-type-specific Ido1 and Ido2 deficiencies differed from that of the global knockout, suggesting that neurons, astrocytes, microglia and macrophages utilize Ido1 and Ido2 to protect against ictogenesis, whereas Ido1 or Ido2 within other cells of the brain or the periphery drive ictogenesis. Thus, peripheral Ido1 and Ido2 may provide a novel target for anti-seizure drug discovery, but input from individual cell types should be carefully considered.