Glutaric acidemia type I (GA-I) is an inborn error of metabolism of
lysine,
hydroxylysine, and
tryptophan, caused by
glutaryl-CoA-dehydrogenase (GCDH) deficiency, characterized by the buildup of toxic organic
acids predominantly in the brain. After acute catabolic states, patients usually develop striatal degeneration, but the mechanisms behind this damage are still unknown.
Quinolinic acid (QA), a metabolite of the
kynurenine pathway, increases especially during
infections/inflammatory processes, and could act synergically with organic
acids, contributing to the neurological features of GA-I. The aim of this study was to investigate whether QA increases seizure susceptibility and modifies brain oscillation patterns in an animal model of GA-I, the Gcdh-/- mice taking high-
lysine diet (Gcdh-/- -Lys). Therefore, the characteristics of QA-induced
seizures and changes in brain oscillatory patterns were evaluated by video-electroencephalography (EEG) analysis recorded in Gcdh-/- -Lys, Gcdh+/+ -Lys, and Gcdh-/- -N (normal diet) animals. We found that the number of
seizures per animal was similar for all groups receiving QA, Gcdh-/- -Lys-QA, Gcdh+/+ -Lys-QA, and Gcdh-/- -N-QA. However, severe
seizures were observed in the majority of Gcdh-/- -Lys-QA mice (82%), and only in 25% of Gcdh+/+ -Lys-QA and 44% of Gcdh-/- -N-QA mice. All Gcdh-/- -Lys animals developed spontaneous recurrent
seizures (SRS), but Gcdh-/- -Lys-QA animals had increased number of SRS, higher mortality rate, and significant predominance of lower frequency oscillations on EEG. Our results suggest that QA plays an important role in the neurological features of GA-I, as Gcdh-/- -Lys mice exhibit increased susceptibility to intrastriatal QA-induced
seizures and long-term changes in brain oscillations.