Hostname: page-component-8448b6f56d-dnltx Total loading time: 0 Render date: 2024-04-23T21:12:30.041Z Has data issue: false hasContentIssue false
  • English
  • Français

The Long and Winding Road to Gamma-Amino-Butyric Acid as Neurotransmitter

Published online by Cambridge University Press:  14 January 2016

Massimo Avoli  and
Krešimir Krnjević
Massimo Avoli*
Affiliation:
Physiology Department, McGill University, Montréal, Quebec, Canada Montreal Neurological Institute and Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada Department of Experimental Medicine, Facoltà di Medicina e Odontoiatria, Sapienza Università di Roma, Roma, Italy.
Krešimir Krnjević
Affiliation:
Physiology Department, McGill University, Montréal, Quebec, Canada
*
Correspondence to: Massimo Avoli, M.D., Ph.D., Montreal Neurological Institute, McGill University, 3801 University Street, Montréal, PQ, Canada, H3A 2B4. E-mail: massimo.avoli@mcgill.ca
Rights & Permissions [Opens in a new window]

Abstract

This review centers on the discoveries made during more than six decades of neuroscience research on the role of gamma-amino-butyric acid (GABA) as neurotransmitter. In doing so, special emphasis is directed to the significant involvement of Canadian scientists in these advances. Starting with the early studies that established GABA as an inhibitory neurotransmitter at central synapses, we summarize the results pointing at the GABA receptor as a drug target as well as more recent evidence showing that GABAA receptor signaling plays a surprisingly active role in neuronal network synchronization, both during development and in the adult brain. Finally, we briefly address the involvement of GABA in neurological conditions that encompass epileptic disorders and mental retardation.

RESUMÉ: Le chemin long et sinueux pour que le GABA soit reconnu comme un neurotransmetteur. Cette revue est axée sur les découvertes réalisées durant plus de six décennies de recherche en neurosciences sur l’acide gamma-aminobutyrique (GABA) comme neurotransmetteur. À cet effet, nous mettons une emphase particulière sur le rôle significatif de chercheurs canadiens dans ce domaine de recherche. En prenant comme point de départ les premières études qui ont établi que le GABA était un neurotransmetteur au niveau de synapses centrales, nous faisons le sommaire des résultats identifiant le récepteur GABA comme étant une cible thérapeutique ainsi que des données plus récentes montrant que la signalisation du récepteur GABAA joue, de façon surprenante, un rôle actif dans la synchronisation du réseau neuronal, tant au cours du développement que dans le cerveau adulte. Finalement, nous traitons brièvement du rôle de GABA dans les maladies neurologiques incluant les troubles épileptiques et l’arriération mentale.

Keywords

Synaptic inhibitionneuronal synchronizationseizuresCl- transportdevelopmentmental retardation.
Type
Review Article
Information
Canadian Journal of Neurological Sciences , Volume 43 , Issue 2 , March 2016 , pp. 219 - 226
Copyright
Copyright © The Canadian Journal of Neurological Sciences Inc. 2016 

More than sixty years after the discovery that gamma-amino-butyric acid (GABA) is a major inhibitory transmitter in the brain, this article reviews its history, with special emphasis on the significant involvement of Canadian scientists. It is now well-established that GABA is the main inhibitory neurotransmitter in the adult forebrain.Reference Martin and Olsen 1 Once released from interneuronal terminals, it activates pre- and postsynaptic GABA receptors, which are categorized into three types: A, B and C.Reference Martin and Olsen 1 , Reference Farrant and Kaila 2 GABAA receptors activate ionotropic anionic channels while GABAB receptors are metabotropic, acting through second messengers. In addition, presynaptic GABAB receptors control transmitter release from excitatory and inhibitory terminals whereas such function remains controversial for GABAA receptors.Reference Draguhn, Axmacher and Kolbaev 3 GABAC receptors, which activate ionotropic channels, are presumably confined to the retina in the adult,Reference Enz, Brandstätter and Hartveit 4 though inhibitory functions in the adult hippocampus have been reported.Reference Alakuijala, Alakuijala and Pasternack 5

GABAA receptors in various regions of the brain have different subunit compositions with specific functional and pharmacological characteristics.Reference Barnard, Skolnick and Olsen 6 , Reference Olsen and Sieghart 7 Moreover, GABAA receptors are located both synaptically (low affinity) and extra-synaptically (high affinity), the latter being activated by spillover of synaptically released GABA; these two categories of receptors are believed to mediate phasic and tonic inhibition, respectively.Reference Semyanov, Walker and Kullmann 8 - Reference Yeung, Canning and Zhu 10 Our review is directed to the early steps that established the function of GABA as an inhibitory neurotransmitterReference Krnjević 11 as well as on more recent evidence pointing to GABAA receptor signaling as a powerful mechanism underlying neuronal network synchronization both during developmentReference Ben-Ari, Gaiarsa and Tyzio 12 and in the adult brain.Reference Avoli and de Curtis 13 Indeed, several studies have identified a paradoxical synchronizing role played by GABAA receptors in cortical structures. Along this road we also discuss the ability of several clinically relevant drugs to modulate GABAergic function and the involvement of this neurotransmitter in neurological disorders.

Establishing GABA as the Major Inhibitory Neurotransmitter

The standard criteria for identification of a neurotransmitter are: (i) its presence in presynaptic neurons; (ii) its release from these presynaptic terminals following activation of these neurons; (iii) its ability to mimic the synaptic response when exogenously applied; and (iv) the ability of agonists or antagonists to enhance or block, respectively, both the response induced by presynaptic terminal activation and that evoked by application of the candidate substance.Reference Obata 14 , Reference Werman 15 It took nearly two decades for GABA to comply with these criteria. Almost simultaneously, in November 1950, three independent studies reported the presence of large amounts of GABA in amphibian and mammalian brains.Reference Awapara, Lanua and Fuerst 16 - Reference Udenfried 18 However, while GABA is readily obtained by alpha-decarboxylation of glutamic acid - the most prominent amino-acid in brain - as an omega amino-acid it cannot be used for the synthesis of proteins and peptides; its function, therefore, remained a matter of speculation for several years.

The first clarifying event came about when the Austrian zoologist Ernst Florey happened to test mammalian brain extracts on the crayfish abdominal stretch receptors.Reference Florey 19 Powerful suppression of the spontaneous firing of the receptor neuron led Florey to conclude that the brain extracts contained a very effective inhibitory agent, which he appropriately named Factor I. To identify the chemical nature of Factor I, he came to Montreal, where there followed several major developments. Working in KAC Elliott’s neurochemistry laboratory at the Montreal Neurological Institute, Hugh McLennan and Florey used the ‘cortical cup’ technique pioneered by Elliott and JasperReference Elliott and Jasper 20 to show that Factor I was released from the cat’s brain in situ Reference Florey and McLennan 21 and that topical applications of Factor I could depress transmission both in sympathetic ganglia and in the lumbar spinal cord.Reference Florey and McLennan 21 , Reference Florey and McLennan 22 Subsequently, after an exhaustive search for active brain constituents, Elliott’s group concluded that GABA accounted for most of Factor I inhibitory action on the crayfish receptor neuron.Reference Bazemore, Elliott and Florey 23 , Reference Bazemore, Elliott and Florey 24 In support of a functional role for GABA came several studies by Herbert Jasper: first, showing depressant effects of GABA on spontaneous spindle waves and evoked potentials obtained with electroencephalogram (EEG) recordings from the cerebral cortex;Reference Iwama and Jasper 25 and then that the release of GABA from the cortex consistently varied with electrographic activity.Reference Jasper, Khan and Elliott 26 , Reference Jasper and Koyama 27

In other respects, further progress was anything but straightforward. In Canada, two of the leaders in the field, Florey and McLennan, found reason to believe that Factor I and GABA were not identical.Reference Florey and McLennan 28 In Australia, following up on these authors’ earlier report demonstrating that Factor I inhibits transmission in the spinal cord, Curtis et al. applied GABA by iontophoresis from micropipettes to a variety of neurons in the feline spinal cord.Reference Curtis, Phillis and Watkins 29 GABA (and some related amino acids) consistently depressed neuronal activity; however, for a number of reasons – including the apparent lack of an inhibitory post-synaptic potential (IPSP)-like hyperpolarizing action and resistance to antagonism by strychnine, known as an effective blocker of spinal inhibition - they concluded that the effects of GABA action were non-specific. A few years later, however, a similar iontophoretic approach, testing single units in the neocortex and cerebellum, led Krnjević and Phillis to propose that GABA was most likely to be the inhibitory transmitter in the brain.Reference Krnjević and Phillis 30 This view was soon supported by the demonstration that (i) the GABA content of individual synaptosomes was sufficient to inhibit cortical cell firingReference Krnjević and Whittaker 31 and (ii) stimulation of the neocortexReference Jasper and Koyama 27 or cerebellumReference Obata and Takeda 32 caused GABA release. Compelling evidence for GABA’s role as inhibitory transmitter came with the demonstration that its effects, when iontophoretically applied to corticalReference Krnjević and Schwartz 33 , Reference Dreifuss, Kelly and Krnjević 34 cuneateReference Galindo, Krnjević and Schwartz 35 and Deiters neuronsReference Obata, Ito, Ochi and Sato 36 , had characteristics (e.g., reversal potentials) similar to those of the IPSPs generated by these cells.

As further mentioned in the following sections, many convulsants act by blocking inhibitory transmission. Indeed, one of the best known, picrotoxin, had proved to be an effective blocker of Factor I and GABA’s inhibitory action on the stretch receptor neuronReference Elliott and Florey 37 , Reference Van der Kloot and Robbins 38 as well as on mammalian brain stem neurons.Reference Galindo 39 , Reference Obata and Highstein 40 Another Canadian, RH Manske - working at the National Research Council Laboratories in Ottawa - had previously discovered bicuculline, the more direct antagonist of GABA receptors, during his systematic investigations of plant alkaloids. In 1933, he identified an unknown compound in the root bulbs of the common Canadian spring flower, Dutchman’s breeches (Dicentra cucularia), which he named bicuculline.Reference Manske 41 Testing samples of bicuculline provided by Manske, pharmacologists at the University of Toronto shortly after found that bicuculline was a powerful convulsant when administered to frogs and rabbits.Reference Welch and Henderson 42 Nothing further happened with bicuculline until 1970 when, after testing various known convulsants, Curtis et al. reported that bicuculline not only blocked inhibition in the central nervous system (CNS) but was a very effective GABA antagonist.Reference Curtis, Duggan and Felix 43 Thus, by the early 1970s, GABA had become widely accepted as the principal inhibitory neurotransmitter, especially in the brain.Reference Nistri and Constanti 44

GABA Receptors as Targets for Drugs

Having established the role of GABA as the main inhibitory transmitter at central synapses, researchers tried to identify the interactions occurring between this receptor and neurotropic drugs or endogenous substances. In the 1970s, several studies revealed that benzodiazepines could enhance GABAergic inhibition in the CNS,Reference Costa, Guidotti and Mao 45 - Reference Choi, Farb and Fischbach 47 and led to the identification of a benzodiazepine site in the GABA receptor.Reference Braestrup and Squires 48 , Reference Möhler and Okada 49 At that time, it was still unclear whether GABA receptors consisted of structurally and functionally different subtypes: the metabotropic GABAB receptor was not discovered before the end of that decade.Reference Bowery, Hill and Hudson 50 Nonetheless, electrophysiological, biochemical and behavioral data clearly indicated that benzodiazepine ligands modulated ionotropic GABAergic function. Subsequent molecular and pharmacological studies demonstrated an allosteric ‘benzodiazepine site’ on most α subunit-containing GABAA receptors.Reference Olsen 51

Over the last four decades, additional agents have been shown to modulate GABAA receptor function and it appears that these actions depend on separate binding sites.Reference Olsen 51 These include, barbiturates (which depress neuronal activity and, at higher doses, may have a direct action on the GABAA receptor),Reference Nicoll 52 - Reference Rho, Donevan and Rogawski 57 steroid metabolitesReference Majewska, Harrison and Schwartz 58 and neurosteroids,Reference Majewska 59 , Reference Belelli and Lambert 60 ethanolReference Nestoros 61 - Reference Wallner, Hanchar and Olsen 63 as well as propofol.Reference Krasowski, Nishikawa and Nikolaeva 64

Decreasing GABA Function Leads to Epileptiform Activity and Seizures

In 1954, two independent groups reported seizures in infants fed with a formula that was accidentally deficient in pyridoxine (also known as vitamin B6); pyridoxine is the coenzyme for the synthesis of GABA from glutamic acid via the enzyme glutamic acid decarboxylase.Reference Coursin 65 , Reference Molony and Parmelee 66 Further studies showed that GABA prevented seizures and that drugs interfering with GABA synthesis could induce convulsions.Reference Hawkins and Sarett 67 , Reference Benassi and Bertolotti 68 This evidence was later corroborated by experiments aimed at identifying the cellular and pharmacological mechanisms underlying epileptiform synchronization. First, it was shown that drugs capable of inducing focal interictal-like discharges preparations in vivo Reference Dichter and Spencer 69 , Reference Ayala, Dichter and Gumnit 70 and in vitro Reference Schwartzkroin and Prince 71 were GABAA receptor antagonists, and that the occurrence of this type of epileptiform activity was characterized by reduction in recurrent and/or feed-forward inhibition.Reference Schwartzkroin and Prince 72 , Reference Dingledine and Gjerstad 73 Second, it was reported that the onset of electrographic seizures induced by repetitive activation of hippocampal inputs are associated with rapid fading of IPSPs.Reference Ben-Ari, Krnjević and Reinhardt 74 Shortly later, Kostopoulos et al. found that cortical recurrent inhibition, which was maintained during an EEG pattern of generalized spike-wave discharge, became markedly reduced before the onset of electrographic tonic-clonic seizures.Reference Kostopoulos, Avoli and Gloor 75 Therefore, early in 1980s, weakening of GABAA receptor signaling was regarded by many neuroscientists as the main cause of seizure activity.

Role of GABA in Synchronizing Adult Neuronal Networks

Early intracellular recordings from thalamic relay cells in vivo highlighted the potential role of presumptive GABAergic IPSPs in causing what was known as rebound excitation, and ultimately leading to low frequency (7-14 Hz) thalamocortical oscillations such as those associated with sleep spindles.Reference Andersen and Andersson 76 , Reference Purpura 77 A major advance in understanding the mechanism of EEG spindles and the switch between waking and sleep came with the demonstration by Steriade’s group at Laval University (Québec) that spindle generation depends on the activity of GABAergic inhibitory neurons in the reticular thalamic nucleus.Reference Steriade, Deschênes and Domich 78 , Reference Steriade, Domich and Oakson 79 Along with the experiments performed in vitro by Llinas,Reference Llinás 80 evidence obtained by several research groups during the last three decades have shown the importance of GABA receptor-mediated IPSPs for hyperpolarizing thalamocortical neurons at membrane potential levels that inactivate low-threshold Ca2+ conductances and activate the Ih current.Reference McCormick and Pape 81 - Reference Crunelli, David and Leresche 84

Depolarizing effects of GABA were identified early in the spinal cord;Reference Eccles, Schmidt and Willis 85 , Reference De Groat, Lalley and Saum 86 but GABAA receptor-activation was later observed in hippocampal pyramidal cells, most often following activation of receptors located on the dendrites.Reference Andersen, Dingledine and Gjerstad 87 , Reference Alger and Nicoll 88 These depolarizing effects were interpreted to reflect a higher concentration of Cl- in the dendrites than in the soma of principal cells, where hyperpolarizations continued to be recorded.Reference Misgeld, Deisz and Dodt 89 Subsequent experiments have shown that GABAA receptor-mediated depolarizations in cortical neurons can also be generated by HCO3 −, which also passes through the anionic channels that are opened during inhibitionReference Kelly, Krnjević and Morris 90 , Reference Bormann, Hamill and Sakmann 91 but with an equilibrium potential more positive than for Cl−.Reference Grover, Lambert and Schwartzkroin 92 - Reference Staley, Soldo and Proctor 94 The depolarizing effect of HCO3 − and K+ efflux and resulting gamma-frequency oscillations are sharply enhanced in the young hippocampus when carbonic anhydrase increases cytoplasmic HCO3 −.Reference Rivera, Voipio and Kaila 95 In addition, these GABAA receptor-mediated, HCO3 −-dependent depolarizations can also activate voltage-gated Ca2+ channels.Reference Autere, Lamsa and Kaila 96

As mentioned in the previous section, studies published between the 1950s and 1980s demonstrated that reducing GABAA receptor signaling can lead to seizures in vivo and interictal-like activity in vitro. This view was challenged by reports that epileptiform synchronization occurs during pharmacological conditions that do not interfere with GABAA receptor function and, in some cases, they appeared to enhance it.Reference Avoli and de Curtis 13 Specifically, epileptiform discharges were observed during application of Mg2+ free-medium in concomitance with the preservation of IPSPs.Reference Mody, Lambert and Heinemann 97 , Reference Tancredi, Hwa and Zona 98 In addition, it was shown that cortical networks made hyperexcitable by reducing the function of specific K+ channels could generate synchronous, propagating neuronal activity, even when ionotropic glutamatergic transmission was blocked.Reference Perreault and Avoli 99 - Reference Dickson and Alonso 102 It was also found that under these pharmacological conditions, each synchronous event was associated with elevations in extracellular potassium ion concentration ([K+]).Reference Avoli, Barbarosie and Lucke 103 - Reference Morris, Obrocea and Avoli 105 Interestingly, shortly before, Mary Morris at the University of Ottawa had found in the hippocampal slice preparation that selective activation of GABAA receptors caused increases in extracellular [K+].Reference Barolet and Morris 106 This finding was later elucidated in Kai Kaila’s laboratory; specifically, it was shown that excessive activation of GABAA receptors leads to accumulation of Cl- inside the postsynaptic cells and to a subsequent increase in K-Cl co-transporter (KCC2) activity that makes K+ and Cl- move to the extracellular space.Reference Viitanen, Ruusuvuori and Kaila 107

GABA Receptor Signaling and High Frequency Oscillations

Synchronization of cortical interneurons also plays a critical role in the generation of fast EEG oscillations in the mature CNS; these include beta-gamma (at 20–80 Hz) and high frequency oscillations (>80 Hz, so called ripples).Reference Buzsáki, Horváth and Urioste 108 Both beta-gamma rhythms and ripples - which are recorded from several cortical structures including those of the limbic system -Reference Murthy and Fetz 109 - Reference Chrobak and Buzsáki 112 are implicated in higher brain processes such as attention, sensorimotor integration, consciousness, learning and memory.Reference Girardeau, Benchenane and Wiener 113 , Reference Montgomery and Buzsáki 114 In vivo studies have shown that ripples represent population IPSPs generated by principal neurons entrained by synchronously active interneuronal networks.Reference Buzsáki, Horváth and Urioste 108 , Reference Chrobak and Buzsáki 112 , Reference Ylinen, Bragin and Nádasdy 115

Similar fast oscillations are reproduced in vitro by bath applying the cholinergic agonist carbachol, high-K+, kainic acid, or metabotropic glutamate receptor agonistsReference Whittington, Traub and Jefferys 116 - Reference Dickson, Biella and de Curtis 119 as well as by electrical tetanic stimulation.Reference Whittington, Stanford and Colling 120 , Reference Bracci, Vreugdenhil and Hack 121 These studies showed that fast activities reflect the synchronization of inhibitory GABAergic networks,Reference Whittington and Traub 122 , Reference Mann and Paulsen 123 with or without the contribution of excitatory glutamatergic networks and gap junctions.Reference Bartos, Vida and Frotscher 124 - Reference Tamás, Buhl and Lörincz 126 The hypothesis that gamma oscillations reflect interactions within interneuron networks is also supported by computer modeling.Reference Wang and Buzsáki 127 , Reference Traub 128

GABA and Brain Maturation

GABAA receptor-mediated depolarizations in the developing CNS were first reported in rabbit hippocampus.Reference Mueller, Chesnut and Schwartzkroin 129 However, depolarizing GABAA receptor-dependent depolarizations were clearly established in immature brain tissue when Ben-Ari et al.Reference Ben-Ari, Cherubini and Corradetti 130 found giant GABAA receptor-mediated depolarizing potentials that were spontaneously generated by rat CA3 pyramidal cells during the first 12 days of postnatal life. It was later shown that, at least in rodents, these GABAergic potentials are consistently recorded during the first post-natal week and that, as the brain matures, they gradually change to hyperpolarization,Reference Cherubini, Gaiarsa and Ben-Ari 131 , Reference Zhang, Spigelman and Carlen 132 which is due to maturation of the outward Cl- transporter KCC2.Reference Rivera, Voipio and Kaila 95 , Reference Rivera, Voipio and Payne 133 In line with this view, synaptic response generated by glycine, which are also Cl- mediated, change from depolarizing to hyperpolarizing during ontogeny.

GABAergic excitation in the immature CNS may play a role in the growth, differentiation, maturation and preservation of neurons as well as in establishing their synaptic connectivity during development.Reference Ben-Ari, Gaiarsa and Tyzio 12 These processes depend on Ca2+ influx that is presumably the main signaling system causing oscillations of cytoplasmic calcium ion concentration and activation of several Ca2+-binding proteins. Since glutamatergic AMPA receptor-type pathways are not operative in the immature brain, GABAA receptor-mediated depolarizing currents in concert with those caused by activation of N-methyl-D-aspartate (NMDA) receptors, which are present quite early on, may cause significant Ca2+ influx.Reference Ben-Ari, Gaiarsa and Tyzio 12

GABA and Tonic Inhibition

Activation of high affinity GABAA receptors, localized extra- or perisynaptically, also causes tonic inhibition; these receptors have distinct, subunit compositions that include the δ α4, α5 and α6 subunits.Reference Semyanov, Walker and Kullmann 8 - Reference Yeung, Canning and Zhu 10 , Reference Nusser, Sieghart and Somogyi 134 - Reference Glykys, Mann and Mody 136 This tonic (‘always on’) current appears to be activated by taurine in the mouse ventrobasal thalamus, thus reducing the excitability of thalamocortical relay neurons.Reference Jia, Yue and Chandra 137 Neurosteroids have been proposed to modulate preferentially tonic rather than phasic inhibition.Reference Belelli and Lambert 60 , Reference Mihalek, Banerjee and Korpi 138 - Reference Lambert, Cooper and Simmons 140 Indeed, neuroactive steroids may play a role in catamenial epilepsy and in temporal lobe epilepsy, as suggested by their ability to delay the establishment of this chronic condition following pilocarpine-induced status epilepticus in rodents.Reference Biagini, Panuccio and Avoli 141

Over the last decade tonic currents have also been proposed to be involved in the potentiating effects of ethanol on GABAA receptor-mediated inhibition.Reference Mody, Glykys and Wei 142 For instance, in the hippocampus, low concentrations of ethanol selectively augment the tonic inhibitory currents mediated by δ subunit-containing GABAA receptors.Reference Wei, Faria and Mody 143 In addition, it has been reported that chronic intermittent ethanol treatment causes a switch of its actions in the hippocampus from extrasynaptic to synaptic GABAA receptors.Reference Liang, Zhang and Cagetti 144

GABA and Neurological Disorders

Dysfunction of GABAA receptor signaling - such as loss or rearrangement of inhibitory interneurons, changes in subunit composition, intracellular ionic homeostasis, etc… - has been documented in several neurological conditions including epileptic disordersReference Olsen, Bureau and Houser 145 - Reference Avoli, Louvel and Pumain 147 and mental retardation conditions such as the Fragile XReference Curia, Papouin and Séguéla 148 - Reference Conde, Palomar and Lama 150 and Down syndromes.Reference Fernandez, Morishita and Zuniga 151 - Reference Deidda, Parrini and Naskar 153 Because a relative excess of GABAergic inhibition may be a factor in conditions associated with memory loss such as aging,Reference Rissman and Mobley 152 the findings that both synaptic plasticity and long term memory can be rescued by agents reducing GABA-mediated inhibitionReference Izquierdo and Medina 154 - Reference Zhu, Huang and Kalikulov 157 indicate potential lines of treatment.

To review all the studies published on these topics is beyond the purpose of this review. However, one should pay attention to the evolving concept of the role played by GABA under some specific pathological conditions such as the generation of seizures in epileptic patients and animal models. For instance, and contrary to expectations from evidence obtained in the 1970s by employing acute models of focal epileptiform discharges,Reference Ayala, Dichter and Gumnit 70 the onset of seizures recorded from epileptic patients undergoing presurgical electrophysiological investigations is characterized by marked reduction of unit firing.Reference Truccolo, Donoghue and Hochberg 158 , Reference Schevon, Weiss and McKhann 159 In addition, recent data obtained from animal models of focal epilepsy, indicate that seizure onset is accompanied by increased activity of inhibitory interneurons that may, in fact, silence principal neurons.Reference Grasse, Karunakaran and Moxon 160 - Reference Toyoda, Fujita and Thamattoor 162 This paradoxical role of inhibition in initiating seizures is in line with evidence obtained from several in vitro and in vivo acute studies that have demonstrated the participation of GABAergic, often depolarizing, currents in both the initiation and maintenance of prolonged periods of epileptiform synchronization.Reference Avoli and de Curtis 13 , Reference Velazquez and Carlen 163 - Reference Fujiwara-Tsukamoto, Isomura and Imanishi 167 The exact mechanisms by which GABAA receptor signaling facilitates seizure activity are still under scrutiny but evidence obtained in vitro from animal preparationsReference Avoli and de Curtis 13 , Reference Avoli, Barbarosie and Lucke 103 , Reference Avoli, Louvel and Kurcewicz 104 and slices of the human dysplastic cortexReference Avoli, Louvel and Pumain 147 point at increases in extracellular [K+] caused by GABA release from interneurons at the onset of seizure activity. It is indeed well established that elevating extracellular [K+] increases excitability and the occurrence of epileptiform discharges both in vivo and in vitro.Reference Zuckermann and Glaser 168 - Reference Traynelis and Dingledine 171 Evidence that GABAA receptor signaling can promote seizures may explain the disappointingly limited efficacy of antiepileptic drugs designed to potentiate GABA receptor-mediated inhibition.

Concluding Remarks

GABA has not ceased to surprise us. Throughout the brain, it is present in, and released from a variety of inhibitory neurons with different characteristics, and it acts on an even greater variety of receptors. Indeed, such major brain structures as the cerebellar cortex and the striatum consist of mostly GABAergic neurons on which depends efficient locomotion. However, albeit well-established, GABA’s inhibitory function can differ greatly according to the type and composition of the targeted receptors and is, moreover, astonishingly malleable. Not only is it susceptible to modulation by a rich variety of drugs - many of which are in extensive clinical use – but, in addition, is characterized by a quite unexpected plasticity, arising from its membrane action, the activation of anionic channels; whether the action is mainly inhibitory or excitatory depends on the predominance of the relative contributions of chloride and bicarbonate ions, and of course the transmembrane Cl- gradient, determined either locally or generally by the direction of net Cl- transport; all these factors are indeed subject to genetic, developmental and pathological changes. These characteristics help to explain why GABA dysfunction is manifested in so many different ways by neurological patients.

Disclosures

Massimo Avoli and Krešimir Krnjević do not have anything to disclose.

References

1. Martin, DL, Olsen, RW. GABA in the Nervous System: The View at Fifty Years. Lippincott Williams & Wilkins, Philadelphia, PA, 2000, P. 1-510.Google Scholar
2. Farrant, M, Kaila, K. The cellular, molecular and ionic basis of GABA(A) receptor signaling. Prog Brain Res. 2007;160:59-87.Google Scholar
3. Draguhn, A, Axmacher, N, Kolbaev, S. Presynaptic ionotropic GABA receptors. Results Probl. Cell Differ. 2008;44:69-85.CrossRefGoogle ScholarPubMed
4. Enz, R, Brandstätter, JH, Hartveit, E, et al. Expression of GABA receptor rho 1 and rho 2 subunits in the retina and brain of the rat. Eur J Neurosci. 1995;7:1495-1501.Google Scholar
5. Alakuijala, A, Alakuijala, J, Pasternack, M. Evidence for a functional role of GABA-C receptors in the rat mature hippocampus. Eur J Neurosci. 2006;23:514-520.CrossRefGoogle ScholarPubMed
6. Barnard, EA, Skolnick, P, Olsen, RW, et al. Subtypes of gamma-aminobutyric acid A receptors: classification on the basis of subunit structure and receptor function. Pharmacol Rev. 1998;50:291-313.Google Scholar
7. Olsen, RW, Sieghart, W. International union of pharmacology. LXX. Subtypes of γ-aminobutyric acid receptors: classification on the basis of subunit composition, pharmacology, and function update. Pharmacol Rev. 2008;60:243-260.CrossRefGoogle ScholarPubMed
8. Semyanov, A, Walker, MC, Kullmann, DM. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat Neurosci. 2003;6:484-490.CrossRefGoogle ScholarPubMed
9. Semyanov, A, Walker, MC, Kullmann, DM, et al. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 2004;27:262-269.CrossRefGoogle ScholarPubMed
10. Yeung, JY, Canning, KJ, Zhu, G, et al. Tonically activated GABAA receptors in hippocampal neurons are high-affinity, low-conductance sensors for extracellular GABA. Mol Pharmacol. 2003;63:2-8.Google Scholar
11. Krnjević, K. How does a little acronym become a big transmitter? Biochem Pharmacol. 2004;68:1549-1555.CrossRefGoogle ScholarPubMed
12. Ben-Ari, Y, Gaiarsa, J-L, Tyzio, R, et al. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007;87:1215-1284.CrossRefGoogle Scholar
13. Avoli, M, de Curtis, M. GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity. Prog Neurobiol. 2011;95:104-132.Google Scholar
14. Obata, K. Biochemistry and physiology of amino acid transmitters. In Handbook of Physiology - The Nervous System I In Kandel, ER, et al. editors. The American Physiological Society, Bethesda, MD, 1977, p. 625-650.Google Scholar
15. Werman, R. Criteria for identification of a central nervous system transmitter. Comp Biochem Physiol. 1966;18:745-766.CrossRefGoogle ScholarPubMed
16. Awapara, J, Lanua, AJ, Fuerst, R, et al. Free gamma-aminobutyric acid in brain. J Biol Chem. 1950;187:35-39.CrossRefGoogle ScholarPubMed
17. Roberts, E, Frankel, S. Gamma-Aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem. 1950;187:55-63.Google Scholar
18. Udenfried, S. Identification of gamma-aminobutyric acid in brain by the isotope derivative method. J Biol Chem. 1950;187:65-69.CrossRefGoogle Scholar
19. Florey, E. An inhibitory and an excitatory factor of mammalian central nervous system, and their action on a single sensory neuron. Arch Int Physiol. 1954;62:33-53.Google Scholar
20. Elliott, KAC, Jasper, HH. Physiological salt solutions for brain surgery; studies of local pH and pial vessel reactions to buffered and unbuffered isotonic solutions. J Neurosurg. 1949;6:140-152.CrossRefGoogle ScholarPubMed
21. Florey, E, McLennan, H. The release of an inhibitory substance from mammalian brain, and its effect on peripheral synaptic transmission. J Physiol (London). 1955;129:384-392.Google Scholar
22. Florey, E, McLennan, H. Effects of an inhibitory factor (factor I) from brain on central synaptic transmission. J Physiol (London). 1955;130:446-455.CrossRefGoogle ScholarPubMed
23. Bazemore, AW, Elliott, KAC, Florey, E. Factor I and gamma amino-butyric acid. Nature. 1956;178:1052-1053.Google Scholar
24. Bazemore, A, Elliott, KA, Florey, E. Isolation of factor I. J Neurochem. 1957;1:334-339.CrossRefGoogle Scholar
25. Iwama, K, Jasper, HH. The action of gamma aminobutyric acid upon cortical electrical activity in the cat. J Physiol. 1957;138:365-380.Google Scholar
26. Jasper, HH, Khan, RT, Elliott, KA. Amino acids released from the cerebral cortex in relation to its state of activation. Science. 1965;147:1448-1449.Google Scholar
27. Jasper, HH, Koyama, I. Rate of release of amino acids from the cerebral cortex in the cat as affected by brainstem and thalamic stimulation. Can J Physiol Pharmacol. 1969;47:889-905.Google Scholar
28. Florey, E, McLennan, H. The effects of factor I and of gamma-aminobutyric acid on smooth muscle preparations. J Physiol (London). 1959;145:66-76.Google Scholar
29. Curtis, DR, Phillis, JW, Watkins, JC. The depression of spinal neurones by γ-aminobutyric acid and β-alanine. J Physiol. 1959;146:185-203.Google Scholar
30. Krnjević, K, Phillis, JW. Iontophoretic studies of neurones in the mammalian cerebral cortex. J Physiol (Lond). 1963;165:274-304.Google Scholar
31. Krnjević, K, Whittaker, VP. Excitation and depression of cortical neurones by brain fractions released from micropipettes. J Physiol (London). 1965;179:298-322.Google Scholar
32. Obata, K, Takeda, K. Release of gamma-aminobutyric acid into the fourth ventricle induced by stimulation of the cat’s cerebellum. J Neurochem. 1969;16:1043-1047.Google Scholar
33. Krnjević, K, Schwartz, S. The action of gamma-aminobutyric acid on cortical neurones. Exp Brain Res. 1967;3:320-336.CrossRefGoogle ScholarPubMed
34. Dreifuss, JJ, Kelly, JS, Krnjević, K. Cortical inhibition and gammaaminobutyric acid. Exp Brain Res. 1969;9:137-154.Google Scholar
35. Galindo, A, Krnjević, K, Schwartz, S. Micro-iontophoretic studies on neurones in the cuneate nucleus. J Physiol (London). 1967;192:359-377.CrossRefGoogle ScholarPubMed
36. Obata, K, Ito, M, Ochi, R, Sato, N. Pharmacological properties of the postsynaptic inhibition by Purkinje cell axons and the action of gamma-aminobutyric acid on Deiters neurones. Exp Brain Res. 1967;4:43-57.CrossRefGoogle ScholarPubMed
37. Elliott, KA, Florey, E. Factor I-inhibitory factor from brain; assay; conditions in brain; simulating and antagonizing substances. J Neurochem. 1956;1:181-192.Google Scholar
38. Van der Kloot, WG, Robbins, J. The effects of gamma-aminobutyric acid and picrotoxin on the junctional potential and the contraction of crayfish muscle. Experientia. 1959;15:35-36.Google Scholar
39. Galindo, A. GABA-picrotoxin interaction in the mammalian central nervous system. Brain Res. 1969;14:763-767.Google Scholar
40. Obata, K, Highstein, SM. Blocking by picrotoxin of both vestibular inhibition and GABA action on rabbit oculomotor neurones. Brain Res. 1970;18:538-541.Google Scholar
41. Manske, RH. The alkaloids of fumariaceous plants. IIIA new alkaloid, bicuculline, and its constitution. Can J Research. 1933;8:142-146.Google Scholar
42. Welch, AD, Henderson, VE. A comparative study of hydrastine, bicuculline and adlumine. J Pharmacol Exp Ther, 34(51):482-491.Google Scholar
43. Curtis, DR, Duggan, AW, Felix, D, et al. GABA, bicuculline and central inhibition. Nature. 1970;226:1222-1224.Google Scholar
44. Nistri, A, Constanti, A. Pharmacological characterization of different types of GABA and glutamate receptors in vertebrates and invertebrates. Prog Neurobiol. 1979;13:117-235.Google Scholar
45. Costa, E, Guidotti, A, Mao, CC. Evidence for involvement of GABA in the action of benzodiazepines: studies on rat cerebellum. Adv Biochem Psychopharmacol. 1975;14:113-130.Google Scholar
46. Haefely, W, Kulcsár, A, Möhler, H, et al. Possible involvement of GABA in the central actions of benzodiazepines. Adv Biochem Psychopharmacol. 1975;(14):131-151.Google Scholar
47. Choi, DW, Farb, DH, Fischbach, GD. Chlordiazepoxide selectively augments GABA action in spinal cord cell cultures. Nature. 1977;269:342-344.CrossRefGoogle ScholarPubMed
48. Braestrup, C, Squires, RF. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H) diazepam binding. Proc Natl Acad Sci USA. 1977;74:3805-3809.CrossRefGoogle ScholarPubMed
49. Möhler, H, Okada, T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977;198:849-851.CrossRefGoogle ScholarPubMed
50. Bowery, NG, Hill, DR, Hudson, AL, et al. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature. 1980;283:92-94.CrossRefGoogle Scholar
51. Olsen, RW. Allosteric ligands and their binding sites define γ-aminobutyric acid (GABA) type A receptor subtypes. Adv Pharmacol. 2015;73:167-202.Google Scholar
52. Nicoll, RA. Pentobarbital: action on frog motoneurons. Brain Res. 1975;96:119-123.Google Scholar
53. Nicoll, RA, Eccles, JC, Oshima, T, et al. Prolongation of hippocampal inhibitory postsynaptic potentials by barbiturates. Nature. 1975;258:625-627.Google Scholar
54. Macdonald, RL, Barker, JL. Enhancement of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons: a common mode of anticonvulsant action. Brain Res. 1979;167:323-336.Google Scholar
55. Olsen, RW. GABA-benzodiazepine-barbiturate receptor interactions. J Neurochem. 1981;37:1-13.Google Scholar
56. Zhang, L, Weiner, JL, Carlen, PL. Potentiation of gamma-aminobutyric acid type A receptor-mediated synaptic currents by pentobarbital and diazepam in immature hippocampal CA1 neurons. J Pharmacol Exp Ther. 1993;266:1227-1235.Google Scholar
57. Rho, JM, Donevan, SD, Rogawski, MA. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol. 1996;497:509-522.Google Scholar
58. Majewska, MD, Harrison, NL, Schwartz, RD, et al. Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science. 1986;232:1004-1007.Google Scholar
59. Majewska, MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol. 1992;38:379-395.CrossRefGoogle ScholarPubMed
60. Belelli, D, Lambert, JJ. Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci. 2005;6:565-575.CrossRefGoogle ScholarPubMed
61. Nestoros, JN. Ethanol specifically potentiates GABA-mediated neurotransmission in feline cerebral cortex. Science. 1980;209:708-710.Google Scholar
62. Aguayo, LG. Ethanol potentiates the GABAA-activated Cl- current in mouse hippocampal and cortical neurons. Eur J Pharmacol. 1990;187:127-130.Google Scholar
63. Wallner, M, Hanchar, HJ, Olsen, RW. Low dose acute alcohol effects on GABAA receptor subtypes. Pharmacol Ther. 2006;112:513-528.CrossRefGoogle Scholar
64. Krasowski, MD, Nishikawa, K, Nikolaeva, N, et al. Methionine 286 in transmembrane domain 3 of the GABAA receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics. Neuropharmacology. 2001;41:952-964.Google Scholar
65. Coursin, DB. Convulsive seizures in infants with pyridoxine-deficient diet. J Am Med Assoc. 1954;154:406-408.CrossRefGoogle ScholarPubMed
66. Molony, CJ, Parmelee, AH. Convulsions in young infats as the result of pyridoxine (vitamin B6) deficiency. J Am Med Assoc. 1954;154:405-406.Google Scholar
67. Hawkins, JE Jr., Sarett, LH. On the efficacy of asparagine, glutamine, gamma-aminobutyric acid and 1-pyrroiidinone in preventing chemically induced seizures in mice. Clin Chim Acta. 1957;2:481-484.CrossRefGoogle ScholarPubMed
68. Benassi, P, Bertolotti, P. Experimental research on the anticonvulsant properties of 1-glutamine, 1-asparagine, gamma-aminobutyric acid and gamma-amino-beta-hydroxybutyric acid. Riv Sper Freniatr Med Leg Alien Ment. 1962;86:342-354.Google Scholar
69. Dichter, M, Spencer, WA. Penicillin-induced interictal discharges from the cat hippocampus. I. Characteristics and topographical features. J Neurophysiol. 1969;32:649-662.Google Scholar
70. Ayala, GF, Dichter, M, Gumnit, , et al. Genesis of epileptic interictal spikes. New knowledge of cortical feedback systems suggests a neurophysiological explanation of brief paroxysms. Brain Res. 1973;52:1-17.Google Scholar
71. Schwartzkroin, PA, Prince, DA. Penicillin-induced epileptiform activity in the hippocampal in vitro preparation. Ann Neurol. 1977;1:463-469.CrossRefGoogle Scholar
72. Schwartzkroin, PA, Prince, DA. Changes in excitatory and inhibitory synaptic potentials leading to epileptogenic activity. Brain Res. 1980;183:61-76.CrossRefGoogle ScholarPubMed
73. Dingledine, R, Gjerstad, L. Reduced inhibition during epileptiform activity in the in vitro hippocampal slice. J Physiol. 1980;305:297-313.Google Scholar
74. Ben-Ari, Y, Krnjević, K, Reinhardt, W. Hippocampal seizures and failure of inhibition. Can J Physiol Pharmacol. 1979;57:1462-1466.CrossRefGoogle Scholar
75. Kostopoulos, G, Avoli, M, Gloor, P. Participation of cortical recurrent inhibition in the genesis of spike and wave discharges in feline generalized penicillin epilepsy. Brain Res. 1983;267:101-112.Google Scholar
76. Andersen, P, Andersson, SA. Physiological Basis of the Alpha Rhythm. New York: Appleton-Century-Crofts; 1968.Google Scholar
77. Purpura, DP. Operations and processes in thalamic and synaptically related neural subsystems. In: Schmitt FO, editor, The Neuroscience: Second Study Program. New York: Rockefeller University Press; 1970, p. 458-470.Google Scholar
78. Steriade, M, Deschênes, M, Domich, L, et al. Abolition of spindle oscillations in thalamic neurons disconnected from nucleus reticularis thalami. J Neurophysiol. 1985;54:1473-1497.Google Scholar
79. Steriade, M, Domich, L, Oakson, G. Reticularis thalami neurons revisited: activity changes during shifts in states of vigilance. J Neurosci. 1986;6:68-81.Google Scholar
80. Llinás, R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science. 1988;242:1654-1664.Google Scholar
81. McCormick, DA, Pape, HC. Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J Physiol (London). 1990;431:291-318.Google Scholar
82. Huguenard, JR, Prince, DA. A novel T-type current underlies prolonged Ca2+-dependent burst firing in GABAergic neurons of rat thalamic reticular nucleus. J Neurosci. 1992;12:3804-3817.Google Scholar
83. Huguenard, JR, McCormick, DA. Thalamic synchrony and dynamic regulation of global forebrain oscillations. Trends Neurosci. 2007;30:350-356.Google Scholar
84. Crunelli, V, David, F, Leresche, N, et al. Role for T-type Ca2+ channels in sleep waves. Pflugers Arch. 2014;466:735-745.Google Scholar
85. Eccles, JC, Schmidt, R, Willis, WD. Pharmacological studies on presynaptic inhibition. J Physiol (London). 1963;168:500-530.Google Scholar
86. De Groat, WC, Lalley, PM, Saum, WR. Depolarization of dorsal root ganglia in the cat by GABA and related amino acids: antagonism by picrotoxin and bicuculline. Brain Res. 1972;44:273-277.Google Scholar
87. Andersen, P, Dingledine, R, Gjerstad, L, et al. Two different responses of hippocampal pyramidal cells to application of gamma-aminobutyric acid. J Physiol. (London). 1980;305:279-296.Google Scholar
88. Alger, BE, Nicoll, RA. Pharmacological evidence for two kinds of GABA receptor on rat hippocampal pyramidal cells studied in vitro. J Physiol. (London). 1982;328:125-141.Google Scholar
89. Misgeld, U, Deisz, RA, Dodt, HU, et al. The role of chloride transport in postsynaptic inhibition of hippocampal neurons. Science. 1986;232:1413-1415.Google Scholar
90. Kelly, JS, Krnjević, K, Morris, ME, et al. Anionic permeability of cortical neurons. Exp Brain Res. 1969;7:11-31.CrossRefGoogle Scholar
91. Bormann, J, Hamill, OP, Sakmann, B. Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones. J Physiol. (London). 1987;385:243-286.Google Scholar
92. Grover, LM, Lambert, NA, Schwartzkroin, PA, et al. Role of HCO3 − ions in depolarizing GABAA receptor-mediated responses in pyramidal cells of rat hippocampus. J Neurophysiol. 1993;69:1541-1555.Google Scholar
93. Kaila, K. Ionic basis of GABAA receptor channel function in the nervous system. Prog Neurobiol. 1994;42:489-537.Google Scholar
94. Staley, KJ, Soldo, BL, Proctor, WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science. 1995;269:977-981.Google Scholar
95. Rivera, C, Voipio, J, Kaila, K. Two developmental switches in GABAergic signalling: the K+-Cl− cotransporter KCC2 and carbonic anhydrase CAVII. J Physiol. 2005;562:27-36.Google Scholar
96. Autere, AM, Lamsa, K, Kaila, K, et al. Synaptic activation of GABAA receptors induces neuronal uptake of Ca2+ in adult hippocampal slices. J Neurophysiol. 1999;81:811-815.CrossRefGoogle Scholar
97. Mody, I, Lambert, JDC, Heinemann, U. Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysiol. 1987;57:869-888.Google Scholar
98. Tancredi, V, Hwa, GG, Zona, C, et al. Low magnesium epileptogenesis in the rat hippocampal slice: electrophysiological and pharmacological features. Brain Res. 1990;511:280-290.Google Scholar
99. Perreault, P, Avoli, M. Physiology and pharmacology of epileptiform activity induced by 4-aminopyridine in rat hippocampal slices. J Neurophysiol. 1991;65:771-785.Google Scholar
100. Perreault, P, Avoli, M. 4-Aminopyridine-induced epileptiform activity and a GABA-mediated long-lasting depolarization in the rat hippocampus. J Neurosci. 1992;12:104-115.Google Scholar
101. Michelson, HB, Wong, RK. Synchronization of inhibitory neurones in the guinea-pig hippocampus in vitro. J Physiol (London). 1994;477:35-45.Google Scholar
102. Dickson, CT, Alonso, A. Muscarinic induction of synchronous population activity in the entorhinal cortex. J Neurosci. 1997;17:6729-6744.Google Scholar
103. Avoli, M, Barbarosie, M, Lucke, A, et al. Synchronous GABA-mediated potentials and epileptiform discharges in the rat limbic system in vitro. J Neurosci. 1996;16:3912-3924.Google Scholar
104. Avoli, M, Louvel, J, Kurcewicz, I, et al. Extracellular free potassium and calcium during synchronous activity induced by 4-aminopyridine in the immature rat hippocampus. J Physiol. (London). 1996;493:707-717.Google Scholar
105. Morris, ME, Obrocea, GV, Avoli, M. Extracellular K+ accumulations and synchronous GABA-mediated potentials evoked by 4-aminopyridine in the adult rat hippocampus. Exp Brain Res. 1996;109:71-82.Google Scholar
106. Barolet, AW, Morris, ME. Changes in extracellular K+ evoked by GABA, THIP and baclofen in the guinea-pig hippocampal slice. Exp Brain Res. 1991;84:591-598.Google Scholar
107. Viitanen, T, Ruusuvuori, E, Kaila, K, et al. The K+-Cl- cotransporter KCC2 promotes GABAergic excitation in the mature rat hippocampus. J Physiol. (London). 2010;588:1527-1540.Google Scholar
108. Buzsáki, G, Horváth, Z, Urioste, R, et al. High-frequency network oscillation in the hippocampus. Science. 1992;256:1025-1027.Google Scholar
109. Murthy, VN, Fetz, EE. Coherent 25- to 35-Hz oscillations in the sensorimotor cortex of awake behaving monkeys. Proc Natl Acad Sci. USA. 1992;89:5670-5674.Google Scholar
110. Singer, W, Gray, CM. Visual feature integration and the temporal correlation hypothesis. Annu Rev Neurosci. 1995;18:555-586.Google Scholar
111. Bragin, A, Jandó, G, Nâdasdy, Z, et al. Gamma (40-100 Hz) oscillation in the hippocampus of the behaving rat. J Neurosci. 1995;15:47-60.Google Scholar
112. Chrobak, JJ, Buzsáki, G. Gamma oscillations in the entorhinal cortex of the freely behaving rat. J Neurosci. 1998;18:388-398.Google Scholar
113. Girardeau, G, Benchenane, K, Wiener, SI, et al. Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci. 2009;12:1222-1223.Google Scholar
114. Montgomery, SM, Buzsáki, G. Gamma oscillations dynamically couple hippocampal CA3 and CA1 regions during memory task performance. Proc Natl Acad Sci. USA. 2007;104:14495-14500.Google Scholar
115. Ylinen, A, Bragin, A, Nádasdy, Z, et al. Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J Neurosci. 1995;15:30-46.Google Scholar
116. Whittington, MA, Traub, RD, Jefferys, JG. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature. 1995;373:612-615.Google Scholar
117. Fisahn, A, Pike, FG, Buhl, EH, Paulsen, O. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro . Nature. 1998;394:186-189.Google Scholar
118. van der Linden, S, Panzica, F, de Curtis, M. Carbachol induces fast oscillations in the medial but not in the lateral entorhinal cortex of the isolated guinea pig brain. J Neurophysiol. 1999;82:2441-2450.Google Scholar
119. Dickson, CT, Biella, G, de Curtis, M. Evidence for spatial modules mediated by temporal synchronization of carbachol-induced gamma rhythm in medial entorhinal cortex. J Neurosci. 2000;20:7846-7854.Google Scholar
120. Whittington, MA, Stanford, IM, Colling, SB, et al. Spatiotemporal patterns of gamma frequency oscillations tetanically induced in the rat hippocampal slice. J Physiol (London). 1997;502:591-607.Google Scholar
121. Bracci, E, Vreugdenhil, M, Hack, SP, et al. On the synchronizing mechanisms of tetanically induced hippocampal oscillations. J Neurosci. 1999;19:8104-8113.Google Scholar
122. Whittington, MA, Traub, RD. Inhibitory interneurons and network oscillations in vitro. Trends Neurosci. 2003;26:676-682.Google Scholar
123. Mann, EO, Paulsen, O. Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci. 2007;30:343-349.Google Scholar
124. Bartos, M, Vida, I, Frotscher, M, et al. Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc Natl Acad Sci. USA. 2002;99:13222-13227.Google Scholar
125. Bartos, M, Vida, I, Jonas, P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat Rev Neurosci. 2007;8:45-56.Google Scholar
126. Tamás, G, Buhl, EH, Lörincz, A, et al. Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons. Nat Neurosci. 2000;3:366-371.Google Scholar
127. Wang, XJ, Buzsáki, G. Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model. J Neurosci. 1996;16:6402-6413.Google Scholar
128. Traub, RD. A model of gamma-frequency network oscillations induced in the rat CA3 region by carbachol in vitro. Eur J Neurosci. 2000;12:4093-4106.Google Scholar
129. Mueller, AL, Chesnut, RM, Schwartzkroin, PA. Actions of GABA in developing rabbit hippocampus: an in vitro study. Neurosci Lett. 1983;39:193-198.Google Scholar
130. Ben-Ari, Y, Cherubini, E, Corradetti, R, et al. Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol. (London). 1989;416:303-325.CrossRefGoogle ScholarPubMed
131. Cherubini, E, Gaiarsa, JL, Ben-Ari, Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 1991;14:515-519.Google Scholar
132. Zhang, L, Spigelman, I, Carlen, PL. Development of GABA-mediated, chloride-dependent inhibition in CA1 pyramidal neurones of immature rat hippocampal slices. J Physiol. 1991;444:25-49.Google Scholar
133. Rivera, C, Voipio, J, Payne, JA, et al. The K+/Cl-co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature. 1999;397:251-255.Google Scholar
134. Nusser, Z, Sieghart, W, Somogyi, P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J Neurosci. 1998;18:1693-1703.Google Scholar
135. Cope, DW, Hughes, SW, Crunelli, V. GABAA receptor-mediated tonic inhibition in thalamic neurons. J Neurosci. 2005;25:11553-11563.Google Scholar
136. Glykys, J, Mann, EO, Mody, I. Which GABAA receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci. 2008;28:1421-1426.Google Scholar
137. Jia, F, Yue, M, Chandra, D, et al. Taurine is a potent activator of extrasynaptic GABA(A) receptors in the thalamus. J Neurosci. 2008;28:106-115.Google Scholar
138. Mihalek, RM, Banerjee, PK, Korpi, ER, et al. Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA. 1999;96:12905-12910.Google Scholar
139. Lambert, JJ, Belelli, D, Peden, DR, et al. Neurosteroid modulation of GABAA receptors. Prog Neurobiol. 2003;71:67-80.Google Scholar
140. Lambert, JJ, Cooper, MA, Simmons, RD, et al. Neurosteroids: endogenous allosteric modulators of GABA(A) receptors. Psychoneuroendocrinology. 2009;34:S48-S58.Google Scholar
141. Biagini, G, Panuccio, G, Avoli, M. Neurosteroids and epilepsy. Curr Opin Neurol. 2010;23:170-176.Google Scholar
142. Mody, I, Glykys, J, Wei, W. A new meaning for “Gin & Tonic”: tonic inhibition as the target for ethanol action in the brain. Alcohol. 2007;41:145-153.Google Scholar
143. Wei, W, Faria, LC, Mody, I. Low ethanol concentrations selectively augment the tonic inhibition mediated by delta subunit-containing GABAA receptors in hippocampal neurons. J Neurosci. 2004;24:8379-8382.Google Scholar
144. Liang, J, Zhang, N, Cagetti, E, et al. Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J Neurosci. 2006;26:1749-1758.Google Scholar
145. Olsen, RW, Bureau, M, Houser, CR, et al. GABA/benzodiazepine receptors in human focal epilepsy. Epilepsy Res. (Suppl.). 1992;8:383-391.Google Scholar
146. Arellano, JI, Munoz, A, Ballesteros-Yanez, I, et al. Histopathology and reorganization of chandelier cells in the human epileptic sclerotic hippocampus. Brain. 2004;127:45-64.Google Scholar
147. Avoli, M, Louvel, J, Pumain, R, et al. Cellular and molecular mechanisms of epilepsy in the human brain. Prog Neurobiol. 2005;77:166-200.Google Scholar
148. Curia, G, Papouin, T, Séguéla, P, et al. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb Cortex. 2009;19:1515-1520.Google Scholar
149. Olmos-Serrano, JL, Paluszkiewicz, SM, Martin, BS, et al. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J Neurosci. 2010;30:9929-9938.Google Scholar
150. Conde, V, Palomar, FJ, Lama, MJ, et al. Abnormal GABA-mediated and cerebellar inhibition in women with the fragile X premutation. J Neurophysiol. 2013;109:1315-1322.Google Scholar
151. Fernandez, F, Morishita, W, Zuniga, E, et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007;10:411-413.Google Scholar
152. Rissman, RA, Mobley, WC. Implication for treatment: GABAA receptors in aging, Down syndrome and Alzheimer’s disease. J Neurochem. 2011;117:613-622.Google Scholar
153. Deidda, G, Parrini, M, Naskar, S, et al. Reversing excitatory GABAAR signaling restores synaptic plasticity and memory in a mouse model of Down syndrome. Nat Med. 2015;21:318-326.Google Scholar
154. Izquierdo, I, Medina, JH. GABAA receptor modulation of memory: the role of endogenous benzodiazepines. Trends Pharmacol Sci. 1991;12:260-265.Google Scholar
155. Abraham, WC, Gustafsson, B, Wigström, H. Single high strength afferent volleys can produce long-term potentiation in the hippocampus in vitro. Neurosci Lett. 1986;70:217-222.Google Scholar
156. Gusev, PA, Alkon, DL. Intracellular correlates of spatial memory acquisition in hippocampal slices: long-term disinhibition of CA1 pyramidal cells. J Neurophysiol. 2001;86:881-899.Google Scholar
157. Zhu, PJ, Huang, W, Kalikulov, D, et al. Suppression of PKR promotes network excitability and enhanced cognition by interferon-γ-mediated disinhibition. Cell. 2011;147:1384-1396.Google Scholar
158. Truccolo, W, Donoghue, JA, Hochberg, LR, et al. Single-neuron dynamics in human focal epilepsy. Nat Neurosci. 2011;14:635-641.Google Scholar
159. Schevon, CA, Weiss, SA, McKhann, G Jr, et al. Evidence of an inhibitory restraint of seizure activity in humans. Nat Communication. 2012;3:1060.Google Scholar
160. Grasse, DW, Karunakaran, S, Moxon, KA. Neuronal synchrony at the transition to spontaneous seizures. Exp Neurol. 2012;248:72-84.Google Scholar
161. Fujita, S, Toyoda, I, Thamattoor, AK, et al. Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy. J Neurosci. 2014;34:16671-16687.Google Scholar
162. Toyoda, I, Fujita, S, Thamattoor, AK, et al. Unit activity of hippocampal interneurons before spontaneous seizures in an animal model of temporal lobe epilepsy. J Neurosci. 2015;35:6600-6618.Google Scholar
163. Velazquez, JL, Carlen, PL. Synchronization of GABAergic interneuronal networks during seizure-like activity in the rat horizontal hippocampal slice. Eur J Neurosci. 1999;11:4110-4118.Google Scholar
164. Köhling, R, Vreugdenhil, M, Bracci, E, et al. Ictal epileptiform activity is facilitated by hippocampal GABAA receptor-mediated oscillations. J Neurosci. 2000;20:6820-6829.Google Scholar
165. Timofeev, I, Grenier, F, Steriade, M. The role of chloride-dependent inhibition and the activity of fast-spiking neurons during cortical spike-wave electrographic seizures. Neuroscience. 2002;114:1115-1132.Google Scholar
166. Derchansky, M, Jahromi, SS, Mamani, M, Shin, DS, Sik, A, Carlen, PL. Transition to seizures in the isolated immature mouse hippocampus: a switch from dominant phasic inhibition to dominant phasic excitation. J Physiol. 2008;586:477-494.Google Scholar
167. Fujiwara-Tsukamoto, Y, Isomura, Y, Imanishi, M, et al. Prototypic seizure activity driven by mature hippocampal fast-spiking interneurons. J Neurosci. 2010;30:13679-13689.Google Scholar
168. Zuckermann, EC, Glaser, GH. Hippocampal epileptic activity induced by localized ventricular perfusion with high-potassium cerebrospinal fluid. Exp Neurol. 1968;20:87-110.Google Scholar
169. Zuckermann, EC, Glaser, GH. Changes in hippocampal-evoked responses induced by localized perfusion with high-potassium cerebrospinal fluid. Exp Neurol. 1968;22:96-117.Google Scholar
170. Jensen, MS, Cherubini, E, Yaari, Y. Opponent effects of potassium on GABAA-mediated postsynaptic inhibition in the rat hippocampus. J Neurophysiol. 1993;69:764-771.Google Scholar
171. Traynelis, SF, Dingledine, R. Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice. J Neurophysiol. 1988;59:259-276.Google Scholar