Increased susceptibility to quinolinic acid-induced seizures and long-term changes in brain oscillations in an animal model of glutaric acidemia type I.

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.

Hippocampal CA1 and cortical interictal oscillations in the pilocarpine model of epilepsy.

Quantitative electroencephalogram analysis has been increasingly applied to study fine changes in brain oscillations in epilepsy. Here we aimed to evaluate interictal oscillations using pilocarpine model of epilepsy to identify changes in network synchronization. We analyzed the in vivo local field potential of two cortical layers (Ctx1, Ctx2) and hippocampal CA1 (stratum oriens-Ors, pyramidale-Pyr, radiatum-Rad and lacunosum-moleculare-LM) in rats, about 5 weeks after pilocarpine injection. Animals that had status epilepticus (SE) and later spontaneous recurrent seizures (SRS) (epileptic animals) exhibited higher delta power recorded in cortical and hippocampal Ors, Rad and LM electrodes. They also had lower power of theta in Ctx1, Ctx2, Ors and LM, lower slow gamma in Ctx1, Ctx2 and Ors, and lower middle and fast gamma power in Ors. NSE animals had higher delta and lower slow gamma power in Ctx1 only, and lower theta power in Ctx1, Ctx2 and LM. Essentially, epileptic animals had higher delta coherence between Ctx1-Ors, Ctx2-Ors, Ctx2-Pyr, Pyr-Ors and stronger phase-amplitude coupling (PAC) between delta and all frequencies in Rad. NSE animals, also had higher delta coherence between Ctx1-Ors and Ctx2-Ors with no changes in PAC, suggesting some cortical network reorganization. Our data suggest an increased synchrony in cortex and CA1 of epileptic animals, particularly for delta frequency with intense delta coupling in Rad, probably an important synchronization site. Understanding the rhythms organization at non-ictal state could provide insights about network connectivity involved in ictogenesis and seizure propagation.

Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I.

OBJECTIVES: Glutaric acidemia type I (GA-I) is an inherited neurometabolic disorder caused by deficiency of glutaryl-CoA dehydrogenase (GCDH) and characterized by increased levels of glutaric, 3-OH-glutaric, and glutaconic acids in the brain parenchyma. The increment of these organic acids inhibits glutamate decarboxylase (GAD) and consequently lowers the γ-aminobutyric acid (GABA) synthesis. Untreated patients exhibit severe neurologic deficits during development, including epilepsy, especially following an acute encephalopathy outbreak. In this work, we evaluated the role of the GABAergic system on epileptogenesis in GA-I using the Gcdh-/- mice exposed to a high lysine diet (Gcdh-/- -Lys). METHODS: Spontaneous recurrent seizures (SRS), seizure susceptibility, and changes in brain oscillations were evaluated by video-electroencephalography (EEG). Cortical GABAergic synaptic transmission was evaluated using electrophysiologic and neurochemical approaches. RESULTS: SRS were observed in 72% of Gcdh-/- -Lys mice, whereas no seizures were detected in age-matched controls (Gcdh+/+ or Gcdh-/- receiving normal diet). The severity and number of PTZ-induced seizures were higher in Gcdh-/- -Lys mice. EEG spectral analysis showed a significant decrease in theta and gamma oscillations and predominant delta waves in Gcdh-/- -Lys mice, associated with increased EEG left index. Analysis of cortical synaptosomes revealed a significantly increased percentage of glutamate release and decreased GABA release in Gcdh-/- -Lys mice that were associated with a decrease in cortical GAD immunocontent and activity and confirmed by reduced frequency of inhibitory events in cortical pyramidal cells. SIGNIFICANCE: Using an experimental model with a phenotype similar to that of GA-I in humans-the Gcdh-/- mice under high lysine diet (Gcdh-/- -Lys)-we provide evidence that a reduction in cortical inhibition of Gcdh-/- -Lys mice, probably induced by GAD dysfunction, leads to hyperexcitability and increased slow oscillations associated with neurologic abnormalities in GA-I. Our findings offer a new perspective on the pathophysiology of brain damage in GA-I.