期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 52, 页码 20944-20948出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0710522105
关键词
Xenopus oocytes; tonic; epileptic rat
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 GABAA receptors. Upon repetitive activation with GABA (1 mM), epileptic GABAA receptors exhibited a GABA(A)-current I-GABA rundown that was significantly enhanced by Zn2+ (<= 250 mu M), and practically abolished by the high-affinity GABAA receptor inverse agonist SR95531 (gabazine; 2.5-25 mu M). 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 mu M) 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据