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

Palma E, Roseti C, Maiolino F, Fucile S, Martinello K, Mazzuferi M, Aronica E, Manfredi M, Esposito V, Cantore G, Miledi R, Simonato M, Eusebi F

Dipartimento di Fisiologia Umana e Farmacologia-Centro di Eccellenza Biologia e Medicina Molecolare, Universita' di Roma "Sapienza," Piazzale A. Moro 5, I00185 Rome, Italy. eleonora.palma@uniroma1.it

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 microM), and practically abolished by the high-affinity GABA(A) receptor inverse agonist SR95531 (gabazine; 2.5-25 microM). 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 microM) 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.

Published 31 December 2007 in Proc Natl Acad Sci U S A, 104(52): 20944-8.
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