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.
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http://dx.doi.org/10.1073/pnas.0710522105 | DOI Listing |
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Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
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Department of Animal Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
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State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, 1 Xiannongtan Street, Xicheng district, Beijing, 100050, China. Electronic address:
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View Article and Find Full Text PDFPharmacol Ther
January 2025
Research Center of Psychiatry and Behavioral Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:
While benzodiazepines have been a mainstay of the pharmacotherapy of anxiety disorders, their short-term efficacy and risk of abuse have driven the exploration of alternative treatment approaches. The endocannabinoid (eCB) system has emerged as a key modulator of anxiety-related processes, with evidence suggesting dynamic interactions between the eCB system and the GABAergic system, the primary target of benzodiazepines. According to the existing literature, the activation of the cannabinoid receptors has been shown to exert anxiolytic effects, while their blockade or genetic deletion results in heightened anxiety-like responses.
View Article and Find Full Text PDFPharmacol Res
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Center for Brain Research, Department of Molecular Neurosciences, Medical University Vienna, Vienna, Austria. Electronic address:
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