GABAA-Current Run-down of Temporal Lobe Epilepsy is Associated with Repetitive Activation of GABAA "Phasic" Receptors

A study was made of the “run-down” of γ-aminobutyric acid (GABAA) receptors, micro-transplanted to Xenopus oocytes from surgically resected brain tissues of patients afflicted with drug-resistant human mesial temporal lobe epilepsy (mTLE). Cell membranes, isolated from mTLE neocortex specimens, were injected into frog oocytes which rapidly incorporated functional GABAA receptors. Upon repetitive activation with GABA (1 mM), “epileptic” GABAA receptors exhibited a GABAA-current (IGABA) run-down that was significantly enhanced by Zn2+ (< 250 μM), and practically abolished by the high-affinity GABAA receptor inverse agonist SR95531 (gabazine, 2.5-25 μM). Conversely, IGABA generated by "control" GABAA receptors micro-transplanted from non-epileptic temporal lobe, lesional TLE or authoptic disease-free tissues, remained stable during repetitive stimulation, even in oocytes treated with Zn2+. We conclude that run-down of mTLE epileptic receptors depends on the presence of “phasic GABAA receptors” that have low sensitivity to antagonism by Zn2+. Additionally, we found that GABAA receptors, micro-transplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, due to pilocarpine-induced status epilepticus, showed greater run-down than control tissue, an event occurring also in patch-clamped rat pyramidal neurons. Run-down of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn2+ (40 μM) and sensitive to the antiepileptic agent levetiracetam, to the neurotrophin brain-derived neurotrophic factor and to the phosphatase blocker okadaic acid. Our findings point to the run-down of GABAA receptors as a hallmark of TLE, and suggest that modulating tonic and phasic mTLE GABAA receptor activity may represent a useful therapeutic approach to the disease.