Abstracts

RATIONALE: In vivo microdialysis studies show that seizure associated glutamate release is doubled in the epileptogenic human hippocampus despite significant neuron loss and gliosis. A semi-quantitative study reported significantly lower cellular glutamate content in the [dsquote]sclerotic-gliotic[dsquote] hippocampi compared to the [dsquote]histologically unremarkable[dsquote] ones. We measured the effects of neuron loss and gliosis on the cellular glutamate, GABA, and glutamine content of the epileptogenic human hippocampus.
METHODS: Twenty patients (eight men) with temporal lobe epilepsy selected for resection of the hippocampus were invited to participate in this project, which was approved by the Yale University Human Investigations Committee. With the blood supply intact (posterior circulation), a sample of the pes of hippocampus was removed and frozen in carbon dioxide snow. Perchloric acid extracts of the small metabolites were prepared and analyzed by proton magnetic resonance spectroscopy at 11.8 Tesla. Adjacent samples were used for cell counts.
RESULTS: Our data, measured in the epileptogenic human hippocampus resected at surgery, was quite remarkable in that it failed to show any significant relationship between the degree of neuronal loss and the cellular content of glutamate, GABA (both major neuronal metabolites), and glutamine (a major glial metabolite). Rank-order regression showed that less than 2% of the variability in cellular metabolite content was accounted for by the four-fold difference in the degree of neuron loss. Mean cellular content of glutamate, GABA, and glutamine was the same in biopsies of hippocampi with the least and most severe neuron loss. Similarly, rank-order regression showed that less than 4% of the variability in cellular metabolite content was accounted for by the two-fold difference in the glial density. Hippocampal glutamate content was above normal in 40% of patients. Above normal glutamate concentrations were measured in hippocampi with the most severe neuron loss and greatest glial density, as well as those with the least neuron loss and gliosis.
CONCLUSIONS: Our findings suggest that cellular glutamate content is increased, probably to above normal levels, in the epileptic human hippocampus. Intracellular glutamate concentrations must be exceedingly high in the remaining glutamatergic neurons or above normal glutamate content must be present in the remaining non-glutamatergic neurons or glia. The high glutamate content would be expected to contribute to the epileptic state by increasing network excitability and promoting excitotoxicity.
[Supported by: NIH-NINDS NS39092]