Extracellular metabolites in the cortex and hippocampus of epileptic patients

Abstract

Interictal brain energy metabolism and glutamate-glutamine cycling are impaired in epilepsy and may contribute to seizure generation. We used the zero-flow microdialysis method to measure the extracellular levels of glutamate, glutamine, and the major energy substrates glucose and lactate in the epileptogenic and the nonepileptogenic cortex and hippocampus of 38 awake epileptic patients during the interictal period. Depth electrodes attached to microdialysis probes were used to identify the epileptogenic and the nonepileptogenic sites. The epileptogenic hippocampus had surprisingly high basal glutamate levels, low glutamine/glutamate ratio, high lactate levels, and indication for poor glucose utilization. The epileptogenic cortex had only marginally increased glutamate levels. We propose that interictal energetic deficiency in the epileptogenic hippocampus could contribute to impaired glutamate reuptake and glutamate-glutamine cycling, resulting in persistently increased extracellular glutamate, glial and neuronal toxicity, increased lactate production together with poor lactate and glucose utilization, and ultimately worsening energy metabolism. Our data suggest that a different neurometabolic process underlies the neocortical epilepsies.

Astrocytes and Epilepsy

“…18 It was subsequently shown that interictal extracellular glutamate levels are also higher in the epileptogenic hippocampus compared to nonepileptogenic ones. 43 The increased interictal basal extracellular glutamate levels negatively correlate with hippocampal volume being significantly increased in the atrophic 43 hippocampus compared to nonatrophic ones. 71 The hippocampal volume negatively correlates with seizure frequency.…”

“…42 Thus, astrocytes in the sclerotic hippocampus seem to have a reduced capacity for glutamine synthesis and ammonia detoxification. Indeed, extracellular glutamine levels 43 and cellular glutamine levels 10,44 are reported reduced in the epileptogenic (sclerotic) hippocampus.…”

“…44 This suggests that in both groups in addition to neurons astrocytes may contain glutamate, and the release of this glutamate during a seizure contributes to the elevated extracellular glutamate levels measured. 18,43 …”

Brain Mitochondrial Metabolic Dysfunction and Glutamate Level Reduction in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice

“…14, 15 We utilized 1 H nuclear magnetic resonance (NMR) spectroscopy and highpressure liquid chromatography (HPLC) to obtain detailed maps of the metabolite content in cerebral cortex and hippocampal formation (HF) in pilocarpine-SE mice. To be able to determine glucose metabolism, we injected animals with [1,[2][3][4][5][6][7][8][9][10][11][12][13] C]glucose 15 minutes before microwave fixation of the head, and evaluated brain extracts using 13 C NMR spectroscopy and gas chromatography-mass spectrometry (GC-MS).…”

De Novo Mutations in YWHAG Cause Early-Onset Epilepsy

“…25 Elevated extracellular glutamate levels have also been reported in animal models of epilepsy and epilepsy patients alike, particularly in individuals with temporal lobe epilepsy. [26][27][28][29] EAAT2 p.Gly82Arg (subject A) substitutes a small hydrophobic and neutrally charged glycine with hydrophilic, positively charged arginine within the cytoplasmic loop joining the first pair of transmembrane domains ( Figure 1). The same substitution is reported in the Epi4K-EPGP dataset in a subject with infantile spasms 4 and two additional individuals with a severe EE, and de novo variants (EAAT2 p.Gly82Arg and p.Leu85Pro) were reported 33 during the preparation of this manuscript.…”