Medial temporal lobe sclerosis is a common pathological finding in patients with medically intractable temporal lobe epilepsy. This disease is characterized by extensive cell loss in the hilus and the hippocampal CA1 and CA3 cell fields in addition to synaptic reorganization throughout the dentate gyrus. 2. The dentate granule cells from hippocampal slices of patients diagnosed with medial temporal lobe sclerosis exhibit reduced synaptic inhibition with concommitant hyperexcitability. These physiological changes were studied relative to the hippocampi of patients with temporal lobe tumors in which the cell loss and synaptic reorganization are not seen. 3. We attempted to determine if this disinhibition was because of changes in the postsynaptic sensitivity to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) by studying the responses to exogenously applied transmitter. As in rodents, the GABA responses in human dentate granule cells studied at the resting membrane potential were depolarizing and were mediated primarily by GABAA receptors. In many cases, these depolarizing GABA responses could trigger action potentials. Thus in some situations, GABA could act as an excitatory neurotransmitter. 4. We found that GABAA receptor-mediated responses in the sclerotic hippocampi were approximately 80% longer than in the comparison population. This difference was not because of changes in either the GABA reversal potential or the GABA-induced conductance change. The data support the hypothesis that the GABA transport system is impaired in sclerotic tissue: application of the GABA uptake inhibitor NNC711 (a tiagibine derivative) greatly prolonged the GABA responses in the tumor-related temporal lobe epilepsy tissue, but had little effect on the sclerotic tissue.
