Hippocampal extracellular GABA correlates with metabolism in human epilepsy

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Abstract

As the major inhibitory neurotransmitter in human brain, GABA is an important modulator of hyperexcitability in epilepsy patients. Given the high energetic cost of neurotransmission and synaptic activity, GABA concentrations may be hypothesized to correlate with metabolic function. We studied human epilepsy patients undergoing intracranial EEG monitoring for seizure localization to examine microdialysis measures of extracellular GABA (ecGABA), pre-operative MR spectroscopic measures of neuronal mitochondrial function (NAA/Cr), and wherever possible, neuropathology and hippocampal volumetry. Two groups undergoing intracranial monitoring for seizure localization were studied: surgically treated hippocampal epilepsy (MTLE) and neocortical (non-hippocampal seizure onset) epilepsy. All data are hippocampal and thus these groups allow comparisons between the epileptogenic and non-epileptogenic regions. ecGABA was measured using in vivo microdialysis performed during intracranial monitoring. Pre-operative in vivo MR spectroscopic imaging was performed to measure the ratio of N-acetyl aspartate (NAA) to creatine. Standard methods for neuropathology and hippocampal volumetry were used. In the neocortical group, increased ecGABA correlated with greater NAA/Cr (R = +0.70, p < 0.015, n = 12) while in the MTLE group, increased ecGABA linked with decreased NAA/Cr (R = −0.94, p < 0.001, n = 8). In MTLE, ecGABA (increased) and NAA/Cr (decreased) correlated with increased glial cell numbers (R = +0.71, p < 0.01, n = 12, R = −0.76 p < 0.03 respectively). No relationship was seen between ecGABA and hippocampal volumes in either group. In epilepsy, ecGABA increases occur across a range of metabolic function. Outside the seizure focus, ecGABA and NAA/Cr increase together; in contrast, within the seizure focus, ecGABA increases with declining mitochondrial function.

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