Extrasynaptic GABAA Receptors: Their Function in the CNS and Implications for Disease

Abstract

Over the past two decades, research has identified extrasynaptic GABAA receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABAA receptors (GABAARs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABAARs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABAAR-mediated conductance. Extrasynaptic GABAARs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery. Over the past two decades, research has identified extrasynaptic GABAA receptor populations that enable neurons to sense the low ambient GABA concentrations present in the extracellular space in order to generate a form of tonic inhibition not previously considered in studies of neuronal excitability. The importance of this tonic inhibition in regulating states of consciousness is highlighted by the fact that extrasynaptic GABAA receptors (GABAARs) are believed to be key targets for anesthetics, sleep-promoting drugs, neurosteroids, and alcohol. The neurosteroid sensitivity of these extrasynaptic GABAARs may explain their importance in stress-, ovarian cycle-, and pregnancy-related mood disorders. Moreover, disruptions in network dynamics associated with schizophrenia, epilepsy, and Parkinson's disease may well involve alterations in the tonic GABAAR-mediated conductance. Extrasynaptic GABAARs may therefore present a therapeutic target for treatment of these diseases, with the potential to enhance cognition and aid poststroke functional recovery. The GABAergic system of the mammalian brain consists of GABA-releasing cells and receptors that bind GABA. GABA-releasing cells are extraordinarily diverse and highly specialized (Freund and Buzsáki, 1996Freund T.F. Buzsáki G. Interneurons of the hippocampus.Hippocampus. 1996; 6: 347-470Crossref PubMed Google Scholar, Klausberger and Somogyi, 2008Klausberger T. Somogyi P. 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GABA(A) receptors: immunocytochemical distribution of 13 subunits in the adult rat brain.Neuroscience. 2000; 101: 815-850Crossref PubMed Scopus (663) Google Scholar), reflecting the existence of various subunit assembly rules and anchoring/trafficking mechanisms (Luscher et al., 2011Luscher B. Fuchs T. Kilpatrick C.L. GABAA receptor trafficking-mediated plasticity of inhibitory synapses.Neuron. 2011; 70: 385-409Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, Vithlani et al., 2011Vithlani M. Terunuma M. Moss S.J. The dynamic modulation of GABA(A) receptor trafficking and its role in regulating the plasticity of inhibitory synapses.Physiol. Rev. 2011; 91: 1009-1022Crossref PubMed Scopus (22) Google Scholar). Following the original description of the GABAAR δ-subunit (Shivers et al., 1989Shivers B.D. Killisch I. Sprengel R. Sontheimer H. Köhler M. Schofield P.R. Seeburg P.H. 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It is also worth noting that a shunting inhibition associated with a tonic conductance could result in a small but persistent membrane depolarization (Farrant and Kaila, 2007Farrant M. Kaila K. The cellular, molecular and ionic basis of GABA(A) receptor signalling.Prog. Brain Res. 2007; 160: 59-87Crossref PubMed Scopus (126) Google Scholar). Another striking feature of the tonic conductance measured in adult neurons is that it represents the simultaneous opening of only a very small fraction of the available extrasynaptic GABAARs (Kasugai et al., 2010Kasugai Y. Swinny J.D. Roberts J.D. Dalezios Y. Fukazawa Y. Sieghart W. Shigemoto R. Somogyi P. Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling.Eur. J. Neurosci. 2010; 32: 1868-1888Crossref PubMed Scopus (38) Google Scholar, Nusser et al., 1995Nusser Z. Roberts J.D. Baude A. Richards J.G. Somogyi P. 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Although tonic inhibition can be generated by a desensitized receptor population as long as receptor number is high, this feature could limit the ability of these receptors to operate as spillover detectors and other less desensitized extrasynaptic GABAARs could be better suited to this role. Slow-rising and slow-decaying IPSCs generated by GABA spillover is a significant feature of GABA release from Ivy/neuorgliaform cells (Capogna and Pearce, 2011Capogna M. Pearce R.A. GABA A,slow: causes and consequences.Trends Neurosci. 2011; 34: 101-112Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, Szabadics et al., 2007Szabadics J. Tamás G. Soltesz I. Different transmitter transients underlie presynaptic cell type specificity of GABAA,slow and GABAA,fast.Proc. Natl. Acad. Sci. USA. 2007; 104: 14831-14836Crossref PubMed Scopus (59) Google Scholar) and has been reported in hippocampal neurons (Vargas-Caballero et al., 2010Vargas-Caballero M. Martin L.J. Salter M.W. Orser B.A. Paulsen O. alpha5 Subunit-containing GABA(A) receptors mediate a slowly decaying inhibitory synaptic current in CA1 pyramidal neurons following Schaffer collateral activation.Neuropharmacology. 2010; 58: 668-675Crossref PubMed Scopus (9) Google Scholar, Zarnowska et al., 2009Zarnowska E.D. Keist R. Rudolph U. Pearce R.A. GABAA receptor alpha5 subunits contribute to GABAA,slow synaptic inhibition in mouse hippocampus.J. Neurophysiol. 2009; 101: 1179-1191Crossref PubMed Scopus (33) Google Scholar). One challenge for the future is to establish whether the spillover currents observed in these and other cell types reflect activation of distinct extrasynaptic GABAAR populations separate from those responsible for generating tonic inhibition (Farrant and Nusser, 2005Farrant M. Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.Nat. Rev. Neurosci. 2005; 6: 215-229Crossref PubMed Scopus (703) Google Scholar). It is now appreciated that in addition to δ-GABAARs, other GABAAR types are also capable of generating a tonic conductance in a number of adult brain regions. Most notably, α5βγ2 subunit-containing GABAARs (α5-GABAARs) generate a tonic conductance that regulates the excitability of pyramidal neurons in CA1 and CA3 regions of the hippocampus (Caraiscos et al., 2004Caraiscos V.B. Elliott E.M. You-Ten K.E. Cheng V.Y. Belelli D. Newell J.G. Jackson M.F. Lambert J.J. Rosahl T.W. Wafford K.A. et al.Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors.Proc. Natl. Acad. Sci. USA. 2004; 101: 3662-3667Crossref PubMed Scopus (269) Google Scholar, Glykys and Mody, 2006Glykys J. Mody I. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice.J. 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Tonically active GABA A receptors: modulating gain and maintaining the tone.Trends Neurosci. 2004; 27: 262-269Abstract Full Text Full Text PDF PubMed Scopus (338) Google Scholar) and layer 5 cortical neurons (Yamada et al., 2007Yamada J. Furukawa T. Ueno S. Yamamoto S. Fukuda A. Molecular basis for the GABAA receptor-mediated tonic inhibition in rat somatosensory cortex.Cereb. Cortex. 2007; 17: 1782-1787Crossref PubMed Scopus (36) Google Scholar). High-affinity GABAARs made up of only αβ subunits are also a possibility (Mortensen and Smart, 2006Mortensen M. Smart T.G. Extrasynaptic alphabeta subunit GABAA receptors on rat hippocampal pyramidal neurons.J. Physiol. 2006; 577: 841-856Crossref PubMed Scopus (65) Google Scholar), as are GABAARs that can open even in the absence of an agonist (Hadley and Amin, 2007Hadley S.H. Amin J. Rat alpha6beta2delta GABAA receptors exhibit two distinct and separable agonist affinities.J. Physiol. 2007; 581: 1001-1018Crossref PubMed Scopus (28) Google Scholar), as reported in some immature neurons (Birnir et al., 2000Birnir B. Everitt A.B. Lim M.S. Gage P.W. Spontaneously opening GABA(A) channels in CA1 pyramidal neurones of rat hippocampus.J. Membr. Biol. 2000; 174: 21-29Crossref PubMed Scopus (29) Google Scholar). It is also possible, given the large number of γ2-GABAARs present in both the synaptic and extrasynaptic membrane (Kasugai et al., 2010Kasugai Y. Swinny J.D. Roberts J.D. Dalezios Y. Fukazawa Y. Sieghart W. Shigemoto R. Somogyi P. Quantitative localisation of synaptic and extrasynaptic GABAA receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling.Eur. J. Neurosci. 2010; 32: 1868-1888Crossref PubMed Scopus (38) Google Scholar, Nusser et al., 1995Nusser Z. Roberts J.D. Baude A. Richards J.G. Somogyi P. Relative densities of synaptic and extrasynaptic GABAA receptors on cerebellar granule cells as determined by a quantitative immunogold method.J. Neurosci. 1995; 15: 2948-2960Crossref PubMed Google Scholar, Soltesz et al., 1990Soltesz I. Roberts J.D. Takagi H. Richards J.G. Mohler H. Somogyi P. Synaptic and Nonsynaptic Localization of Benzodiazepine/GABAA Receptor/Cl- Channel Complex Using Monoclonal Antibodies in the Dorsal Lateral Geniculate Nucleus of the Cat.Eur. J. Neurosci. 1990; 2: 414-429Crossref PubMed Scopus (24) Google Scholar), that more conventional low-affinity GABAARs make a contribution to the steady-state conductance when ambient GABA concentrations are high (Farrant and Kaila, 2007Farrant M. Kaila K. The cellular, molecular and ionic basis of GABA(A) receptor signalling.Prog. Brain Res. 2007; 160: 59-87Crossref PubMed Scopus (126) Google Scholar). Nevertheless, it is now appreciated that specific high-affinity GABAAR populations, such as δ-GABAARs and α5-GABAARs, are predominantly responsible for generating the tonic conductance found in many brain regions under normal physiological conditions. The study of these extrasynaptic GABAAR populations is now entering a defining stage and this review focuses on new insights into the potential involvement of these receptors in the cellular and molecular abnormalities underlying neurological and psychiatric disorders including sleep disturbances, stress-related psychiatric conditions, and epilepsy. We also further discuss the potential role of these receptors in cognition, in recovery from stroke, and in mediating the effects of alcohol. Adequate sleep is essential for our well being, and many neuropsychiatric conditions, such as depression and schizophrenia, are associated with severe disruptions in sleep patterns. It is thus disappointing that we understand little about the mechanisms that control sleep and rely on limited repertoires of clinical interventions to treat sleep disorders (Wafford and Ebert, 2008Wafford K.A. Ebert B. Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time.Nat. Rev. Drug Discov. 2008; 7: 530-540Crossref PubMed Scopus (37) Google Scholar). GABAARs play a pivotal role in the control of our sleep rhythms, and for many decades benzodiazepines and zolpidem, known for their ability to potentiate GABAAR currents, have remained the most widely prescribed treatment for insomnia, in spite of producing tolerance, addiction, and withdrawal problems. In a search for more refined drug interventions, it has become clear that the hypnotic actions of the sleep promoting drug gaboxadol (Wafford and Ebert, 2006Wafford K.A. Ebert B. Gaboxadol—a new awakening in sleep.Curr. Opin. Pharmacol. 2006; 6: 30-36Crossref PubMed Scopus (65) Google Scholar) (4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol; THIP) can be attributed to this drug's selective action on δ-GABAARs (Brown et al., 2002Brown N. Kerby J. Bonnert T.P. Whiting P.J. Wafford K.A. Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.Br. J. Pharmacol. 2002; 136: 965-974Crossref PubMed Scopus (324) Google Scholar). At concentrations of around 500 nM, this drug activates δ-GABAARs with little action on synaptic GABAAR types. This selectivity arises from gaboxadol's lower apparent affinity at γ2-GABAARs compared to δ-GABAARs (Mortensen et al., 2010Mortensen M. Ebert B. Wafford K. Smart T.G. Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.J. Physiol. 2010; 588: 1251-1268Crossref PubMed Scopus (40) Google Scholar). Gaboxadol acts as a hypnotic in humans to increase sleep duration by promoting slow-wave or non-rapid eye movement (non-REM) sleep (Faulhaber et al., 1997Faulhaber J. Steiger A. Lancel M. The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans.Psychopharmacology (Berl.). 1997; 130: 285-291Crossref PubMed Scopus (100) Google Scholar). When δ-GABAARs are removed by genetic manipulations in mice, gaboxadol-induced slow oscillations are absent from the EEG (Winsky-Sommerer et al., 2007Winsky-Sommerer R. Vyazovskiy V.V. Homanics G.E. Tobler I. The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors.Eur. J. Neurosci. 2007; 25: 1893-1899Crossref PubMed Scopus (33) Google Scholar) and the anesthetic potency of gaboxadol is reduced (Boehm et al., 2006Boehm 2nd, S.L. Homanics G.E. Blednov Y.A. Harris R.A. delta-Subunit containing GABAA receptor knockout mice are less sensitive to the actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol.Eur. J. Pharmacol. 2006; 541: 158-162Crossref PubMed Scopus (23) Google Scholar). Unfortunately, due to side-effects such as hallucinations and disorientation in a subset of patients, gaboxadol failed phase III clinical trials as an alternative to benzodiazepines, but more potent δ-GABAAR selective agonists are being developed (Wafford et al., 2009Wafford K.A. van Niel M.B. Ma Q.P.