scholarly journals Distinct regulation of tonic GABAergic inhibition by NMDA receptor subtypes

2021 ◽  
Author(s):  
Kunwei Wu ◽  
David Castellano ◽  
Qingjun Tian ◽  
Wei Lu
Keyword(s):  
Hippocampal Neurons ◽  
Tonic Inhibition ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Brain Functions ◽  
Acute Seizures ◽  
Pathological Conditions ◽  
Acid Type ◽  
Acute Seizure ◽  
Critical Link

Tonic inhibition mediated by extrasynaptic gamma-aminobutyric acid type A receptors (GABAARs) play important roles in the regulation of various brain functions. However, the regulatory mechanisms for tonic inhibition remain largely unknown. Here we report distinct actions of GluN2A- and GluN2B-containing subtypes of NMDA receptors (NMDARs) on tonic inhibition in hippocampal neurons. Mechanistically, GluN2A- and GluN2B-containing NMDARs play differential roles in alpha5-GABAAR internalization. Additionally, GluN2A-, but not GluN2B-, containing receptors are required for the homeostatic potentiation of tonic inhibition. In an acute seizure model induced by kainic acid, tonic inhibition is decreased during acute seizures, while it is increased 24 h later, and these alterations are dependent on the distinct GluN2-containing NMDARs. Collectively, these data reveal a critical link between NMDARs and extrasynaptic GABAARs in both physiological and pathological conditions.

Opposing Actions of Etomidate on Cortical Theta Oscillations Are Mediated by Different γ-Aminobutyric Acid Type A Receptor Subtypes

2005 ◽  
Vol 102 (2) ◽  
pp. 346-352 ◽  
Author(s):  
Berthold Drexler ◽  
Claire L. Roether ◽  
Rachel Jurd ◽  
Uwe Rudolph ◽  
Bernd Antkowiak
Keyword(s):  
Gabaa Receptors ◽  
Type A ◽  
Mutant Mice ◽  
Theta Oscillations ◽  
Aminobutyric Acid ◽  
Receptor Subtypes ◽  
Gamma Aminobutyric Acid ◽  
Wild Type ◽  
Action Potential Firing ◽  
Acid Type

Background Cortical networks generate diverse patterns of rhythmic activity. Theta oscillations (4-12 Hz) are commonly observed during spatial learning and working memory tasks. The authors ask how etomidate, acting predominantly via gamma-aminobutyric acid type A (GABAA) receptors containing beta2 or beta3 subunits, affects theta activity in vitro. Methods To characterize the effects of etomidate, the authors recorded action potential firing together with local field potentials in slice cultures prepared from the neocortex of the beta3(N265M) knock-in mutant and wild type mice. Actions of etomidate were studied at 0.2 microm, which is approximately 15% of the concentration causing immobility ( approximately 1.5 microm). Results In preparations derived from wild type and beta3(N265M) mutant mice, episodes of ongoing activity spontaneously occurred at a frequency of approximately 0.1 Hz and persisted for several seconds. Towards the end of these periods, synchronized oscillations in the theta band developed. These oscillations were significantly depressed in slices from beta3(N265M) mutant mice (P < 0.05). In this preparation etomidate acts almost exclusively via beta2 subunit containing GABAA receptors. In contrast, no depression was observed in slices from wild type mice, where etomidate potentiates both beta2- and beta3-containing GABAA receptors. Conclusions At concentrations assumed to cause sedation and amnesia, etomidate depresses theta oscillations via beta2-containing GABAA receptors but enhances these oscillations by acting on beta3 subunit containing receptors. This indicates that the overall effect of the anesthetic reflects a balance between enhancement and inhibition produced by different GABAA receptor subtypes.

scholarly journals Clustering of Extrasynaptic GABAAReceptors Modulates Tonic Inhibition in Cultured Hippocampal Neurons

2004 ◽  
Vol 279 (44) ◽  
pp. 45833-45843 ◽  
Author(s):  
Enrica Maria Petrini ◽  
Ivan Marchionni ◽  
Paola Zacchi ◽  
Werner Sieghart ◽  
Enrico Cherubini
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Prolonged Exposure ◽  
Tonic Inhibition ◽  
Aminobutyric Acid ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Acid Type ◽  
Ambient Gaba ◽  
Cultured Hippocampal Neurons

Tonic inhibition plays a crucial role in regulating neuronal excitability because it sets the threshold for action potential generation and integrates excitatory signals. Tonic currents are known to be largely mediated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that are persistently activated by submicromo-lar concentrations of ambient GABA. We recently reported that, in cultured hippocampal neurons, the clustering of synaptic GABAAreceptors significantly affects synaptic transmission (Petrini, E. M., Zacchi, P., Barberis, A., Mozrzymas, J. W., and Cherubini, E. (2003)J. Biol. Chem.278, 16271–16279). In this work, we demonstrated that the clustering of extrasynaptic GABAAreceptors modulated tonic inhibition. Depolymerization of the cytoskeleton with nocodazole promoted the disassembly of extrasynaptic clusters of δ and γ2subunit-containing GABAAreceptors. This effect was associated with a reduction in the amplitude of tonic currents and diminished shunting inhibition. Moreover, diffuse GABAAreceptors were less sensitive to the GAT-1 inhibitor NO-711 and to flurazepam. Quantitative analysis of GABA-evoked currents after prolonged exposure to submicromolar concentrations of GABA and model simulations suggest that clustering affects the gating properties of extrasynaptic GABAAreceptors. In particular, a larger occupancy of the singly and doubly bound desensitized states can account for the modulation of tonic inhibition recorded after nocodazole treatment. Moreover, comparison of tonic currents recorded during spontaneous activity and those elicited by exogenously applied low agonist concentrations allows estimation of the concentration of ambient GABA. In conclusion, receptor clustering appears to be an additional regulating factor for tonic inhibition.

Cardiovascular Complications of Sleep Disorders: A Better Night’s Sleep for a Healthier Heart / From Bench to Bedside

2020 ◽  
Vol 19 (2) ◽  
pp. 210-232 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Evdoxia J. Apostolopoulos ◽  
Helen Melita ◽  
Antonis S. Manolis
Keyword(s):  
Sleep Disorders ◽  
Disease Risk ◽  
Behavioral Therapy ◽  
Benzodiazepine Receptor ◽  
Cardiovascular Complications ◽  
Gamma Aminobutyric Acid ◽  
Acid Type ◽  
Increased Risk ◽  
Cv Disease ◽  
Meta Analyses

: Sleep is essential to and an integral part of life and when lacking or disrupted, a multitude of mental and physical pathologies ensue, including cardiovascular (CV) disease, which increases health care costs. Several prospective studies and meta-analyses show that insomnia, short (<7h) or long (>9h) sleep and other sleep disorders are associated with an increased risk of hypertension, metabolic syndrome, myocardial infarction, heart failure, arrhythmias, CV disease risk and/or mortality. The mechanisms by which insomnia and other sleep disorders lead to increased CV risk may encompass inflammatory, immunological, neuro-autonomic, endocrinological, genetic and microbiome perturbations. Guidelines are emerging that recommend a target of >7 h of sleep for all adults >18 years for optimal CV health. Treatment of sleep disorders includes cognitive-behavioral therapy considered the mainstay of non-pharmacologic management of chronic insomnia, and drug treatment with benzodiazepine receptor agonists binding to gamma aminobutyric acid type A (benzodiazepine and non-benzodiazepine agents) and some antidepressants. However, observational studies and meta-analyses indicate an increased mortality risk of anxiolytics and hypnotics, although bias may be involved due to confounding and high heterogeneity in these studies. Nevertheless, it seems that the risk incurred by the non-benzodiazepine hypnotic agents (Z drugs) may be relatively less than the risk of anxiolytics, with evidence indicating that at least one of these agents, zolpidem, may even confer a lower risk of mortality in adjusted models. All these issues are herein reviewed.

[11C]Flumazenil Positron Emission Tomography Analyses of Brain Gamma-Aminobutyric Acid Type A Receptors in Angelman Syndrome

2008 ◽  
Vol 152 (4) ◽  
pp. 546-549.e3 ◽  
Author(s):  
Naoko Asahina ◽  
Tohru Shiga ◽  
Kiyoshi Egawa ◽  
Hideaki Shiraishi ◽  
Shinobu Kohsaka ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Angelman Syndrome ◽  
Type A ◽  
Emission Tomography ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Positron Emission ◽  
Acid Type
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