GABA(A)-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABA(A) "phasic" receptors

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 Zn²⁺ (≤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 Zn²⁺. We conclude that rundown of mTLE epileptic receptors depends on the presence of “phasic GABA_A receptors” that have low sensitivity to antagonism by Zn²⁺. 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 Zn²⁺ (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.