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

Abstract

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.

• Authors: Eleonora Palma, Cristina Roseti, Francesca Maiolino, Sergio Fucile, Katiuscia Martinello, Manuela Mazzuferi, Eleonora Aronica, Mario Manfredi, Vincenzo Esposito, Gianpaolo Cantore, Ricardo Miledi, Michele Simonato, Fabrizio Eusebi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 52 Pg. 20944-8 (Dec 26 2007) ISSN: 1091-6490 [Electronic] United States
• PMID: 18083839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, GABA-A
• Pilocarpine
• Okadaic Acid
• gamma-Aminobutyric Acid
• Zinc

Topics

• Animals
• Electrophysiology (methods)
• Epilepsy, Temporal Lobe (metabolism)
• Humans
• Male
• Neurons (metabolism)
• Okadaic Acid (pharmacology)
• Oocytes (metabolism)
• Pilocarpine (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, GABA-A (metabolism, physiology)
• Sensitivity and Specificity
• Temporal Lobe (pathology)
• Xenopus
• Zinc (chemistry)
• gamma-Aminobutyric Acid (metabolism)