Altered hippocampal kynurenine pathway metabolism contributes to hyperexcitability in human mesial temporal lobe epilepsy-hippocampal sclerosis.

BACKGROUND AND PURPOSE: Glutamate receptor-mediated enhanced excitatory neurotransmission is typically associated with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Kynurenic acid and quinolinic acid are two important tryptophan-kynurenine pathway metabolites that modulate glutamate receptor activity. This study was designed to test the hypothesis that alteration in metabolism of tryptophan-kynurenine pathway metabolites in the hippocampus of patients with MTLE-HS contributes to abnormal glutamatergic transmission.

EXPERIMENTAL APPROACH: Levels of tryptophan-kynurenine pathway metabolites were determined using HPLC and LC-MS/MS in hippocampal samples from patients with MTLE-HS, compared with autopsy and non-seizure control samples. mRNA and protein expressions of tryptophan-kynurenine pathway enzymes were determined by qPCR and Western blot. Spontaneous glutamatergic activities were recorded from pyramidal neurons in the presence of kynurenine and kynurenic acid, using whole-cell patch clamp.

KEY

RESULTS

Levels of kynurenic acid were reduced and quinolinic acid levels were raised in hippocampal samples from MTLE-HS patients, whereas kynurenine levels remained unaltered, compared with levels in non-seizure controls. Spontaneous glutamatergic activity in MTLE-HS hippocampal samples was higher than that in non-seizure controls. Treatment with kynurenine inhibited glutamatergic activity in non-seizure control samples but not in MTLE-HS samples. However, exogenously applied kynurenic acid inhibited glutamatergic activity in both non-seizure control and MTLE-HS hippocampal samples. Also, levels of kynurenine aminotransferase II and its cofactor pyridoxal phosphate were reduced in MTLE-HS samples.

CONCLUSION AND IMPLICATIONS: Our findings indicate that altered metabolism of tryptophan-kynurenine pathway metabolites in hippocampus could contribute to hyperglutamatergic tone in patients with MTLE-HS.