Brain concentrations of glutamate and GABA in human epilepsy: A review

An imbalance between excitation and inhibition has been a longstanding proposed mechanism regarding ictogenesis and epileptogenesis. This imbalance is related to increased extracellular glutamate in the brain and/or reduction in GABA concentrations, leading to excitotoxicity, seizures, and cell death. This review aims to summarize the microdialysis and magnetic resonance spectroscopy (MRS) literature investigating glutamate and GABA concentrations in epilepsy patients, present limitations, and suggest future directions to help direct the search for novel epilepsy treatments. The majority of microdialysis studies demonstrated increased glutamate in epileptic regions either compared to control regions or to baseline levels; however, sample sizes were small, with some statistical comparisons missing. For the MRS research, two of six studies reported significant changes in glutamate levels compared to controls, though the results were mixed, with one reporting increased and the other reporting decreased glutamate levels. Eleven of 20 studies reported significant changes in Glx (glutamate + glutamine) or Glx ratios, with most reporting increased levels, except for a few epilepsy syndromes where reduced levels were reported. Few studies investigated GABA concentrations, with one microdialysis and four spectroscopy studies reporting increased GABA levels, and one study reporting decreased GABA in a different brain region. Based on this review, future research should account for medication use; include measurements of GABA, glutamate, and glutamine; use high-tesla strength MRI; and further evaluate the timing of microdialysis. Understanding the importance of brain glutamate and GABA levels in epilepsy may provide direction for future therapies and treatments.