GABA uptake regulates cortical excitability via cell type–specific tonic inhibition

Semyanov, Alexey; Walker, Matthew C.; Kullmann, Dimitri M.

doi:10.1038/nn1043

Cited by 377 publications

(470 citation statements)

References 46 publications

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“…During the last decade, several studies have shown that GABA A receptor activation can also mediate tonic inhibition; these receptors are extrasynaptically and perisynaptically localized and contain a distinct, high affinity subunit composition made of δ and α4, α5 & α6 subunits (Nusser et al, 1998;Yeung et al, 2003;Semyanov et al, 2003Semyanov et al, , 2004Cope et al, 2005;Scimemi et al, 2005;Glykys et al, 2008). Hence, GABA A receptors can generate two types of current, depending on their location and subunit composition: the first type is the classic synaptic phasic (or 'transient') current that results from the release of GABA from synaptic vesicles in the synaptic cleft; the second type is a tonic ('always on') current that is caused by GABA A receptors responding to low levels of ambient GABA (Farrant and Nusser, 2005).…”

Section: Gaba a Receptor-mediated Tonic Inhibitionmentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABA A receptormediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABA A receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABA A receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABA A receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABA A receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well.

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Section: Gaba a Receptor-mediated Tonic Inhibitionmentioning

confidence: 99%

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Avoli¹,

Curtis²

2011

Progress in Neurobiology

227

253

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“…Tonic inhibition mediated by extrasynaptic, δ subunit-containing GABARs has been identified in a number of neurons [31][32][33][34][35] and is thought to regulate neuronal excitability; however, the role of tonic inhibition in shaping behavior is unclear. The results reported here were obtained from cerebellar granule cells, a cell type for which there is strong evidence that receptors containing α6 and δ subunits are extrasynaptic 16,19,36 and are required for tonic GABA current 20,21 .…”

Section: Link Between Tonic Inhibition and Behaviormentioning

confidence: 99%

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

et al. 2005

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Neuronal mechanisms underlying alcohol intoxication are unclear. We find that alcohol impairs motor coordination by enhancing tonic inhibition mediated by a specific subtype of extrasynaptic GABA A receptor (GABAR), α6β3δ, expressed exclusively in cerebellar granule cells. In recombinant studies, we characterize a naturally occurring single-nucleotide polymorphism that causes a single amino acid change (R100Q) in α6 (encoded in rats by the Gabra6 gene). We show that this change selectively increases alcohol sensitivity of α6β3δ GABARs. Behavioral and electrophysiological comparisons of Gabra6 100R/100R and Gabra6 100Q/100Q rats strongly suggest that alcohol impairs motor coordination by enhancing granule cell tonic inhibition. These findings identify extrasynaptic GABARs as critical targets underlying low-dose alcohol intoxication and demonstrate that subtle changes in tonic inhibition in one class of neurons can alter behavior.Humans have been consuming alcohol for thousands of years, and the use of alcoholic beverages pervades human culture and society and can have substantial health effects 1 . Different mechanisms by which ethanol might depress brain function have been proposed based on ethanol's ability to modulate a wide variety of ion channels 2-4 , neurotransmitter receptors 5-10 and transporters 11 . Among these diverse targets, however, GABARs are arguably the most attractive candidates. This is in part because other classes of known GABAR modulators such as benzodiazepines, barbiturates and certain anesthetics lead to behavioral effects that closely resemble ethanol intoxication. Yet despite strong evidence implicating GABARs in ethanol's action, critical details remain unclear. For instance, although it is known that native GABARs are heteropentamers assembled from 19 possible subunits 12,13 , it has not been possible to link the activity of particular GABAR subunits to changes in behavioral sensitivity to ethanol.Recent studies suggest that specific combinations of GABAR subunits (those containing α4β3δ and α6β3δ) are uniquely sensitive to ethanol, showing dose dependencies that mirror blood alcohol levels associated with intoxication in humans 9,10 . GABARs containing α4 and δ subunits are expressed in many brain regions 14,15 , but α6 is found in only two types of neurons (cerebellar granule cells and granule cells in the cochlear nucleus) and is expressed together with δ only in cerebellar granule cells 14,16,17 . In granule cells α6 and δ combine with β subunits Correspondence should be addressed to M.W. (mwallner@mednet.ucla.edu) or T.S.O. (otist@ucla.edu). 3 These authors contributed equally to this work. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We set out to examine whether such extrasynaptic GABARs containing α6 and δ subunits account for behavioral effects of ethanol at moderately intoxicating doses. To link these particular GABARs to behavioral sensitivity, we first characterized a naturally occurring single-nucleotide polymo...

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“…It has recently been shown that low concentrations of extracellular GABA may result in persistent or 'tonic' activation of extrasynaptic GABA A receptors in hippocampal interneurons, the cerebellum, and the dentate gyrus (Farrant and Nusser, 2005;Kullmann et al, 2005;Semyanov et al, 2003). Other than δ, no GABA A receptor subunits have so far been found to be exclusively extrasynaptic (Farrant and Nusser, 2005).…”

Section: Presynaptic Postsynaptic and Extrasynaptic Receptors: Phasimentioning

confidence: 99%

The role of GABAA receptors in the development of alcoholism

Enoch

2008

Pharmacology Biochemistry and Behavior

197

181

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Alcoholism is a common, heritable, chronic relapsing disorder. GABA A receptors undergo allosteric modulation by ethanol, anesthetics, benzodiazepines and neurosteroids and have been implicated in the acute as well as the chronic effects of ethanol including tolerance, dependence and withdrawal. Medications targeting GABA A receptors ameliorate the symptoms of acute withdrawal. Ethanol induces plasticity in GABA A receptors: tolerance is associated with generally decreased GABA A receptor activation and differentially altered subunit expression. The dopamine (DA) mesolimbic reward pathway originating in the ventral tegmental area (VTA), and interacting stress circuitry play an important role in the development of addiction. VTA GABAergic interneurons are the primary inhibitory regulators of DA neurons and a subset of VTA GABA A receptors may be implicated in the switch from heavy drinking to dependence. GABA A receptors modulate anxiety and response to stress; important elements of sustained drinking and relapse. The GABA A receptor subunit genes clustered on chromosome 4 are highly expressed in the reward pathway. Several recent studies have provided strong evidence that one of these genes, GABRA2, is implicated in alcoholism in humans. The influence of the interaction between ethanol and GABA A receptors in the reward pathway on the development of alcoholism together with genetic and epigenetic vulnerabilities will be explored in this review.

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GABA uptake regulates cortical excitability via cell type–specific tonic inhibition

Cited by 377 publications

References 46 publications

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

Alcohol-induced motor impairment caused by increased extrasynaptic GABAA receptor activity

The role of GABAA receptors in the development of alcoholism

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