ArticleThe European journal of neuroscience2013
Disrupted Cl(-) homeostasis contributes to reductions in the inhibitory efficacy of diazepam during hyperexcited states.
Article in The European journal of neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 38 citations in OpenAlex.
- Synaptic correlates of benzodiazepine tolerance.Molecular psychiatry · 2026Review
- Article
- The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal CliScience · 2024Article
- Uncovering novel KCC2 regulatory motifs through a comprehensive transposon-based mutant library.Frontiers in molecular neuroscience · 2024Article
- Direct activation of KCC2 arrests benzodiazepine refractory status epilepticus and limits the subsequent neuronal injury in mice.Cell reports. Medicine · 2023Article
- Cortical Parvalbumin-Positive Interneuron Development and Function Are Altered in the APC Conditional Knockout Mouse Model of Infantile and Epileptic Spasms Syndrome.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- The amygdala lesioning due to status epilepticus - Changes in mechanisms controlling chloride homeostasis.Clinics (Sao Paulo, Brazil) · 2023Article
- Why won't it stop? The dynamics of benzodiazepine resistance in status epilepticus.Nature reviews. Neurology · 2022Review
- Article
- Excitatory GABAergic signalling is associated with benzodiazepine resistance in status epilepticus.Brain : a journal of neurology · 2019Article
- Developmentally regulated KCC2 phosphorylation is essential for dynamic GABA-mediated inhibition and survival.Science signaling · 2019Article
- Mannitol decreases neocortical epileptiform activity during early brain development via cotransport of chloride and water.Neurobiology of disease · 2019Article
- Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods.Cognitive, affective & behavioral neuroscience · 2018Article
- The small molecule CLP257 does not modify activity of the KNature medicine · 2017Article
- Behavioral disinhibition and antiepileptic treatment in childhood epilepsy: A retrospective cohort study.Epilepsia open · 2017Article
- Regulation of neuronal chloride homeostasis by neuromodulators.The Journal of physiology · 2016Review
- Bumetanide reduces seizure progression and the development of pharmacoresistant status epilepticus.Epilepsia · 2016Article
- Selective inhibition of KCC2 leads to hyperexcitability and epileptiform discharges in hippocampal slices and in vivo.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- K-Cl cotransporter KCC2--a moonlighting protein in excitatory and inhibitory synapse development and function.Pflugers Archiv : European journal of physiology · 2015Review
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The K(+) -Cl(-) cotransporter type 2 is the major Cl(-) extrusion mechanism in most adult neurons. This process in turn leads to Cl(-) influx upon activation of γ-aminobutyric acid type A (GABAA ) receptors and the canonical hyperpolarising inhibitory postsynaptic potential. Several neurological disorders are treated with drugs that target and enhance GABAA receptor signaling, including the commonly used benzodiazepine diazepam and the anesthetic propofol. Some of these disorders are also associated with deficits in GABAA signaling and become less sensitive to therapeutic drugs that target GABAA receptors. To date, it is unknown if alterations in the neuronal Cl(-) gradient affect the efficacies of diazepam and propofol. We therefore used the in vitro model of glutamate-induced hyperexcitability to test if alterations in the Cl(-) gradient affect the efficacy of GABAA modulators. We exclusively utilised the gramicidin perforated-patch-clamp configuration to preserve the endogenous Cl(-) gradient in rat neurons. Brief exposure to glutamate reduced the inhibitory efficacy of diazepam within 5 min, which was caused by the collapse of the Cl(-) gradient, and not due to reductions in GABAA receptor number. Unlike diazepam, propofol retained its efficacy by shunting the membrane conductance despite the glutamate-induced appearance of depolarising GABAA -mediated currents. Similarly, pharmacological inhibition of K(+) -Cl(-) cotransporter type 2 by furosemide disrupted Cl(-) homeostasis and reduced the efficacy of diazepam but not propofol. Collectively our results suggest that pathological hyperexcitable conditions could cause the rapid accumulation of intracellular Cl(-) and the appearance of depolarising GABAA -mediated currents that would decrease the efficacy of diazepam.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.