GABA uptake and heterotransport are impaired in the dentate gyrus of epileptic rats and humans with temporal lobe sclerosis

In vivo dialysis and in vitro electrophysiological studies suggest that GAB A uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomic al studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably d ue to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under seve ral conditions, including elevations in [K+]o, which occurs during seizures . Thus GABA transporters could contribute to seizure termination and propag ation through heterotransport. To test whether GABA transport is compromise d in both the forward (uptake) and reverse (heterotransport) direction in t he sclerotic epileptic dentate gyrus, the physiological effects of microapp lied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-ind uced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- a nd NPA-induced responses were prolonged in granule cells from epileptic rat s versus controls (51.3 and 31.3% increase, respectively) while the conduct ance change evoked with NPA microapplication was reduced by 40%. Furthermor e the ratio of GABA/NPA conductance, but not duration, was significantly > 1 in epileptic rats but not controls, suggesting a compromise in transporte r function in both directions. Similar changes were observed in tissue rese cted from epileptic patients with medial temporal sclerosis but not in thos e without the anatomical changes associated with MTLE. These data suggest t hat the GABA transporter system is functionally compromised in both the for ward and reverse directions in the dentate gyrus of chronically epileptic t issue characterized by mesial temporal sclerosis. This alteration may enhan ce inhibitory tone interically yet be permissive for seizure propagation du e to a decreased probability for GABA heterotransport during seizures.