Cited by 427Neuroscience and Neuropharmacology ResearchEpilepsy research and treatmentNeural dynamics and brain function

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Rapid Seizure-Induced Reduction of Benzodiazepine and Zn 2+ Sensitivity of Hippocampal Dentate Granule Cell GABA A Receptors

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Kapur, Jaideep, Macdonald, Robert L.·1997·The Journal of Neuroscience

DOI 10.1523/jneurosci.17-19-07532.1997PMC PMC2892718

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Abstract

Fast synaptic inhibition in the forebrain is mediated primarily by GABA acting on GABAA receptors (GABARs). GABARs are regulated by numerous positive (barbiturates, benzodiazepines, and neurosteroids) and negative (picrotoxin, bicuculline, and Zn2+) allosteric modulators. The sensitivity of GABARs to GABA and to allosteric modulators changes gradually during normal development, during development of chronic epilepsy, and after prolonged exposure to GABAR agonists. Here we report the development of rapid functional plasticity of GABARs occurring over 45 min of continuous seizures (status epilepticus) in rats. Seizures induced in rats by administration of lithium followed by pilocarpine were readily terminated by the benzodiazepine diazepam when administered early during the seizures (after 10 min of seizures). However, during status epilepticus, there was a substantial reduction of diazepam potency for termination of the seizures. To determine whether the loss of sensitivity of the animals to diazepam was caused by an alteration of GABAR functional properties, we obtained whole-cell GABAR currents from hippocampal dentate granule cells isolated acutely from control rats and from rats undergoing status epilepticus. GABAR properties were characterized by determining GABA sensitivity and the sensitivity of GABARs to regulation by benzodiazepines, barbiturates, and Zn2+. When compared with those from naive controls, GABAR currents from rats undergoing status epilepticus were less sensitive to diazepam and Zn2+ but retained their sensitivity to GABA and pentobarbital. We conclude that the prolonged seizures of status epilepticus rapidly altered the functional properties of hippocampal dentate granule cell GABARs.

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Authors: Kapur, J., & Macdonald, R. L.
Affiliations: Pediatrics and Genetics (US)
University of Michigan (US)
ORCID: Kapur, Jaideep
Macdonald, Robert L.
Venue: The Journal of Neuroscience
Publisher: Society for Neuroscience
Published: 1997-10-01
Volume: 17
Issue: 19
Pages: 7532-7540
ISSN: 0270-6474 (ISSN-L)
1529-2401
DOI: 10.1523/jneurosci.17-19-07532.1997
PMC: PMC2892718
OpenAlex: W1909177474
Cited by: 427
References: 61
Citations by year: 2026: 5 · 2025: 10 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 16 · 2020: 11 · 2019: 16 · 2018: 21 · 2017: 28 · 2016: 18 · 2015: 26 · 2014: 14 · 2013: 11 · 2012: 18
FWCI: 3.81
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-sa
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 182 d)
Locations: Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Epilepsy Foundation
U.S. Public Health Service (R01 33300)
National Institute of Neurological Disorders and Stroke (KO8-NS01748, K08NS001748, R01NS033300)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords: GABAA receptor, status epilepticus, benzodiazepine sensitivity, diazepam, zinc, allosteric modulation, barbiturates, pentobarbital, functional plasticity, chronic epilepsy
MeSH terms: Animals, Benzodiazepines, Diazepam, Electric Conductivity, Female, Male, Neurons, Pentobarbital, Receptors, GABA-A, Seizures, Time Factors, Zinc, Rats, Sprague-Dawley, Dentate Gyrus, Rats, GABA-A Receptor Antagonists

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Rapid Seizure-Induced Reduction of Benzodiazepine and Zn 2+ Sensitivity of Hippocampal Dentate Granule Cell GABA A Receptors

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