A study was made of the “rundown” of GABA _A receptors, microtransplanted 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 that rapidly incorporated functional GABA _A receptors. Upon repetitive activation with GABA (1 mM), “epileptic” GABA _A receptors exhibited a GABA _A -current ( I _GABA ) rundown that was significantly enhanced by Zn ²⁺ (≤250 μM), and practically abolished by the high-affinity GABA _A receptor inverse agonist SR95531 (gabazine; 2.5–25 μM). Conversely, I _GABA generated by “control” GABA _A receptors microtransplanted from nonepileptic temporal lobe, lesional TLE, or authoptic disease-free tissues remained stable during repetitive stimulation, even in oocytes treated with Zn ²⁺ . We conclude that rundown of mTLE epileptic receptors depends on the presence of “phasic GABA _A receptors” that have low sensitivity to antagonism by Zn ²⁺ . Additionally, we found that GABA _A receptors, microtransplanted from the cerebral cortex of adult rats exhibiting recurrent seizures, caused by pilocarpine-induced status epilepticus, showed greater rundown than control tissue, an event also occurring in patch-clamped rat pyramidal neurons. Rundown of epileptic rat receptors resembled that of human mTLE receptors, being enhanced by Zn ²⁺ (40 μM) and sensitive to the antiepileptic agent levetiracetam, the neurotrophin brain-derived neurotrophic factor, and the phosphatase blocker okadaic acid. Our findings point to the rundown of GABA _A receptors as a hallmark of TLE and suggest that modulating tonic and phasic mTLE GABA _A receptor activity may represent a useful therapeutic approach to the disease.