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Noebels JL, Avoli M, Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US); 2012.

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Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition.

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Tonic GABAA Receptor-Mediated Signaling in Epilepsy

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GABAA receptors can mediate a “tonic” form of signaling that is not time-locked to presynaptic action potentials, and which depends upon detection of ambient GABA by extrasynaptic receptors. This form of signaling is cell type specific. In dentate granule cells, it is positively modulated by endogenous neurosteroids, which undergo changes related to hormonal status and stress.

Tonic currents profoundly modulate the input–output relationships of individual neurons. However, tonic currents can have a paradoxical excitatory role, either by depolarizing neurons or via a network effect (because of a dominant effect on interneurons). Tonic currents hyperpolarize thalamocortical neurons and so modulate their firing pattern from regular to burst firing.

Tonic currents are preserved or increased in models of focal epilepsy, even in the face of a loss of synaptic inhibition. This may represent a compensatory change that prevents seizure generation. Tonic currents are increased in animal models of absence epilepsy, and promote the generation of spike-wave discharges. Some substances selectively target tonic currents, including certain anesthetics, neurosteroids and gaboxadol. Drugs that elevate the ambient GABA concentration, including the antiepileptic drugs tiagabine and vigabatrin, also potentiate tonic currents, contributing both to their antiepileptic and to their pro-absence effects.

Fast inhibitory signaling in the brain has conventionally been considered to be predominantly mediated by the vesicular release of GABA from presynaptic terminals onto post-synaptic GABAA receptors.1 Transient opening of such receptors results in a brief increase in postsynaptic permeability to Cl, generating an inhibitory postsynaptic potential (IPSP) that reduces the probability of firing of the neuron. However, there is abundant evidence that GABA can also act relatively far from its site of release, and this, together with several other discoveries in the last two decades, has contributed to a re-appraisal of the roles of GABAA receptors in modulating neuronal and circuit excitability.1

Much of the new understanding of GABAergic transmission comes from in vitro brain slice experiments, which allow direct postsynaptic recording of IPSPs or, by voltage-clamping the postsynaptic neuron, inhibitory postsynaptic currents (IPSCs). Importantly, during the synchronous activation of many synapses, sufficient GABA can “spill” out of the synapse to activate extra-synaptic GABAA and also metabotropic GABAB receptors, prolonging the IPSP.2,3 This may serve to dampen excessive network activity. More recently, a slower form of signaling has been described in which high affinity, slowly desensitizing GABAA receptors detect low concentrations of ambient GABA in the extracellular space even in the absence of evoked release. This has been termed tonic GABAA receptor mediated inhibition (Figure 1).1,4

Figure 1. Voltage-clamp recording from a dentate gyrus granule cell in the presence of glutamate receptor blockers.

Figure 1

Voltage-clamp recording from a dentate gyrus granule cell in the presence of glutamate receptor blockers. Inhibitory post-synaptic currents (IPSCs) are represented by phasic inward currents (downward deflections) which are inhibited by the GABAA receptor (more...)

Tonic GABAA receptor activity was evident in some of the first patch-clamp studies of GABAergic inhibition in the rodent hippocampus5, and were later described in layer III cells of somatosensory cortical slices.6 In these and other studies, application of a GABAA receptor antagonist reduced the resting membrane conductance and produced a shift in the baseline “holding” current required to clamp neurons at a given membrane potential (Figure 1). Shortly afterwards, GABAA receptor mediated tonic currents were described in cerebellar granule cells.7,8 Application of GABAA receptor antagonists in this preparation not only resulted in a shift in the baseline current but also decreased the background noise, consistent with block of stochastic channel openings. These tonic currents are both developmentally regulated and cell-type specific.1,4 Indeed, in some neurons, the tonic current represents a greater proportion of the total GABAA receptor mediated current than that mediated by spontaneous synaptic activity. 1,4

Although the tonic activity of GABAA receptors is often termed “tonic inhibition”, it is important to bear in mind that GABAA receptors do not always inhibit neurons. Opening of these receptors has two main effects: a membrane potential change and a decrease in membrane resistance. The membrane potential change caused by opening of GABAA receptors depends on the electrochemical gradients for Cl, and to a lesser extent, HCO3 ions which also move through the open channel.9 Irrespective of whether the receptors are activated phasically (by local presynaptic exocytosis) or tonically (by ambient GABA), these gradients determine if GABAA receptors de- or hyperpolarize the neuron. In mature neurons, GABAA receptors are generally hyperpolarizing, but early in development, they can be depolarizing because the intracellular Cl concentration is high.9 These voltage changes further interact with sub-threshold voltage-dependent conductances, and propagate within dendrites. GABAA receptor opening also shunts excitatory inputs by decreasing the resistance of the membrane, and this provides an additional mechanism that reduces the excitability of the post-synaptic cell irrespective of whether GABAergic signaling is de- or hyper-polarizing.


GABAA receptors are pentameric structures composed of five subunits from a possible choice of 19 subunits.10 Other than those containing the ρ subunit (which form a separate class of “GABAC” receptors), GABAA receptors usually consist of two (from a repertoire of 6) α subunits, two (from 3) β subunits, and another subunit (usually a γ or δ subunit). There are thousands of possible subunit combinations; however only relatively few are expressed with any frequency in the mammalian central nervous system. The specific subunit combinations confer different channel conductances, affinities for GABA, and kinetics. Moreover, different subunits alter the response of the receptors to endogenous and exogenous modulators, including Zn2+ and neurosteroids. The sub-cellular location of GABAA receptors (synaptic versus extrasynaptic) is also determined by subunit composition. As a general rule γ subunits are required for synaptic expression; however γ subunit containing receptors are also found extrasynaptically.11 δ-subunit containing GABAA receptors, in contrast, are exclusively extrasynaptic. The β subunit may also play a role in determining the location, trafficking and pharmacology of GABAA receptors.12 Importantly, the receptors mediating tonic currents are different from those contributing to the peak synaptic currents and tend to have a high affinity for GABA, desensitize slowly and incompletely in the presence of the agonist, and are probably located extrasynaptically. However, as hinted above, the distinction between receptors mediating phasic and tonic inhibition is blurred, because during intense synaptic activity, exocytosed GABA can diffuse out of the synaptic cleft and overwhelm transporters to activate peri- and extra- synaptic receptors.13,14

Among the receptor subtypes that contribute to tonic signaling are α4βxδ receptors, which have been proposed to mediate the tonic current in dentate granule cells15–17 and thalamocortical neurons18–20, and α6βxδ receptors that mediate the tonic current in cerebellar granule cells.8,16,21 Other receptor subtypes may also mediate tonic currents, including α5βxγx receptors in CA1 pyramidal cells22 and ɛ-containing receptors in hypothalamic neurons.23 The ɛ-subunit containing GABAA receptors, which occur not only in the hypothalamus but also in the amygdala and locus coerelus, are of specific interest in this regard, as they can open spontaneously in the absence of GABA, but desensitize with high concentrations of GABA.23 This leads to the prediction that tonic GABAA receptor-mediated currents in these brain structures should be paradoxically “turned off” by increases in extracellular GABA. It is likely that other GABAA receptor subunit combinations are also expressed extrasynaptically and are able to mediate a tonic current. Some whole-cell patch-clamp data complemented by single channel recordings support the presence of a zolpidem-sensitive GABAA receptor that can mediate a tonic current in the hippocampus, implying the presence of α1, α2 or α3 with a γ subunit.24,25 These subunit combinations are not usually associated with high affinity, extrasynaptic receptors, but rather low affinity, synaptic receptors. Receptors with unusual subunit composition, such as αxβ3 without either γ or δ have also been inferred on the basis of sensitivity to GABA and Zn2+ as well as single channel conductance.26 These studies serve to illustrate our lack of knowledge of the full range of GABAA receptor subtypes, a situation that is not helped by the poor availability of subtype-specific agonists and antagonists. Moreover, there is growing evidence that within one cell type (e.g. CA1 pyramidal cells, dentate gyrus granule cells and interneurons), more than one receptor subtype may contribute to the tonic current.25,27–31 A heterogeneous population of receptors with different affinities mediating tonic current increases the number of potential modulators and also extends the range of extracellular GABA concentrations that can modulate excitability of the neuron.


The physiological importance of tonic GABAA receptor-mediated currents is supported by the finding that genetic deletion of the α6 subunit, resulting in the absence of tonic inhibition in cerebellar granule cells, leads to a compensatory up-regulation of two-pore K+ channels to restore the resting membrane conductance.32 There is also considerable evidence that tonic currents mediate a qualitatively different form of inhibition from that generated by synaptic currents. Clearly, tonic currents provide a form of signaling over a different time-scale than that mediated by phasic synaptic currents. Although the mechanisms that modulate tonic conductances are poorly understood, it is likely that they fluctuate only relatively slowly, on a timescale of seconds to days. Among mechanisms that have been reported to modulate tonic inhibition are alterations in receptor expression, variations in extracellular GABA concentrations, changes in endogenous neuromodulators (in particular neurosteroids), and a variety of neuroactive drugs, both therapeutic and recreational4. Thus, tonic GABAA receptor-mediated signaling is far more than a background leak conductance, and the developmental and computational roles of tonic signaling in different neurons are beginning to attract attention.

Tonically active GABAA receptors have been detected in embryonic neocortical cells in situ in the ventricular zone33, prior to synapse formation in hippocampal principal cells.34 Currents mediated by these receptors have, therefore, been hypothesized to play a part in neuronal development. This hypothesis has received further support from the observation of tonic currents in developing dentate gyrus granule cells; these currents are depolarizing because of the high intracellular chloride concentration, and have been suggested to have a trophic effect, promoting dendritic development.35

In neurons where the Cl reversal potential is close to the resting membrane potential, the major effect of tonically active GABAA receptors is to increase the membrane conductance. This will reduce the membrane time constant4, and at the same time attenuate rapid fluctuations in membrane voltage arising from the action of excitatory synapses. The consequences for the computational properties of individual neurons are difficult to predict. In particular, spontaneous fluctuations in membrane potential play an important role in setting the slope or gain of the input-output relationship of a neuron.36–39 Information is encoded in very different ways in different brain circuits, and the effect of the tonic conductance on the input-output relationship is likely to depend on whether information is represented as changes in the rate of firing of individual neurons (“rate coding”) or as changes in the recruitment of neurons to firing threshold (“sparse coding”).39 For small neurons that use rate coding (such as cerebellar granule cells), there is convincing evidence that the gain of the input-output slope is sensitive to tonic inhibition.36,39 In contrast, tonic inhibition has less effect on the gain of the input-output function of a complex neuron that uses sparse coding (such as a hippocampal pyramidal cell), and instead has a larger effect on the offset of the input-output curve (Figure 2).37,39 Such an effect on offset is further promoted by a strong outward rectification of the tonic current in hippocampal pyramidal cells.37 This effect on excitability may contribute to increasing the threshold for induction of long term potentiation.40 These considerations provide a possible explanation for the finding that genetic ablation or pharmacological reduction of tonic currents mediated by α5 subunits, which contribute to tonic currents in hippocampal pyramidal cells, increases the rate of spatial learning.41–43 However, this increased rate of learning may be at the expense of a general increase in the probability of a neuron to fire, loss of sparse network activity, and consequently a decrease in the ability to discriminate different input patterns.

Figure 2. The input-output function of a pyramidal cell can be represented by the probability of neuronal firing plotted against the amplitude of the input (black curve).

Figure 2

The input-output function of a pyramidal cell can be represented by the probability of neuronal firing plotted against the amplitude of the input (black curve). Synaptic noise reduces the gain (slope) of the input-output function because inputs that would (more...)

Tonically active GABAA receptors not only shunt excitatory currents, but also affect the membrane potential. In many neurons in the adult brain GABAA receptors hyperpolarize the membrane, and this aspect of tonic currents further reduces neuronal firing. However, in situations in which GABAA receptor-mediated currents are strongly depolarizing, tonic current can have a paradoxical excitatory effect by bringing neurons closer to action potential threshold. Tonic activation of presynaptic GABAA receptors on mossy fiber terminals has such a depolarizing effect, promoting glutamate release and long-term potentiation.44 Furthermore, in the thalamus the hyperpolarizing effect of tonic currents can change the firing pattern of thalamocortical neurons from a regular firing to a burst-firing pattern19, which is important for the generation of sleep rhythms (such as slow waves during deep sleep) and also for absence seizures (see below).

To understand the network effects of tonic GABAA signaling, it is also necessary to consider its relative magnitude in different cells types.4,25 Under baseline conditions in vitro, the GABAA receptor-mediated tonic current in hippocampal interneurons is considerably larger than the current mediated by spontaneous IPSCs, and thus is an important determinant of interneuron excitability.25 In keeping with this, a low concentration of picrotoxin that relatively selectively inhibits tonic currents significantly increases the frequency of spontaneous IPSCs in hippocampal pyramidal cells. These findings suggest that tonic conductances in interneurons act as a homeostatic regulator of synaptic inhibition of principal cells: if the ambient GABA concentration decreases, interneurons become more excitable, resulting in an increase in the frequency of GABA receptor-mediated IPSCs in pyramidal cells.25 Conversely, an increase in ambient GABA concentration would be expected to render interneurons relatively less excitable, leading to a decrease in synaptic inhibition, while tonic inhibition of pyramidal neurons increases (Figure 3). What are the likely network consequences of a shift from synaptic to tonic inhibition in pyramidal cells? The decrease in synaptic inhibition would be expected to decrease membrane voltage fluctuations and therefore to increase the gain of the neuron’s input amplitude-firing probability curve, and at the same time to shift it to the left (decrease offset). However, this shift due to the decrease in synaptic inhibition may be more than compensated by the increase in tonic inhibition.37 The net effect would therefore be to increase neuronal gain while maintaining or increasing the offset.37 Interestingly, extracellular GABA has been shown to increase in the hippocampus when an animal is stressed or exposed to a new environment45,46, and by increasing neuronal gain such an effect is likely to promote neuronal firing and long term potentiation, whilst the increase in neuronal offset prevents indiscriminate neuronal firing.

Figure 3. Tonic GABAA receptor-mediated currents in interneurons of the hippocampus are relatively larger and more sensitive to low ambient GABA concentrations than are currents in pyramidal cells.

Figure 3

Tonic GABAA receptor-mediated currents in interneurons of the hippocampus are relatively larger and more sensitive to low ambient GABA concentrations than are currents in pyramidal cells. As the GABA concentration increases, interneurons become less excitable (more...)

Cell-type specificity has also been reported in the thalamus; tonic GABAA receptor-mediated currents are present in thalamocortical neurons but not in the reticular thalamic neurons.18,19 The thalamocortical neurons gate sensory input into the neocortex, whilst the reticular thalamic neurons are inhibitory and provide the main synaptic inhibitory drive onto thalamocortical neurons. Therefore, in contrast to the hippocampus, the synaptic inhibitory currents onto thalamocortical neurons are likely to remain unaltered by a local increase in extracellular GABA.

Tonic inhibition likely plays a role in numerous other brain functions. For example, in the striatum, tonic GABAA receptor-mediated signaling has been shown to be larger in D2 dopamine receptor-expressing spiny stellate cells that project to the globus pallidum (the so-called “indirect” pathway), than in D1-expressing cells in the “direct” pathway that project to the substantia nigra.47 This difference appears to result from a complex interplay of expression of α5 subunits and β3 phosphorylation by protein kinase A, which itself is activated or inhibited by D1 and D2 receptors respectively.48 These findings provide a mechanism for dopamine release to shift the balance of strength of signaling via the direct and indirect pathways.


Tonic GABAA receptor currents have been described in dentate granule cells15,49, hippocampal pyramidal cells50 and hippocampal interneurons.25 The receptors predominantly mediating tonic current in these three cell types are different. In CA1 pyramidal cells, the receptors are predominantly those containing α5 and γ subunits22, whilst in dentate granule cells, the tonic current is predominantly mediated by receptors containing α4 and δ subunits.16 δ subunits also contribute to tonic currents in interneurons.51

Neurosteroids increase the efficacy of GABAA receptors containing the δ subunit52 and thus increase tonic conductances.16,53 Indeed, the synthetic neurosteroid ganaxolone has entered clinical trial for the treatment of epilepsy.54 In addition, neurosteroids alter δ and α4 subunit expression.55,56 This effect appears to depend upon the length of exposure, with short-term exposure to allopregnalone resulting in increased subunit expression and increased tonic currents in dentate granule cells57, whilst longer-term exposure can result in subunit and GABAA receptor down-regulation.58 Short-term increases in neurosteroids occur with acute stress and during the menstrual cycle, and it is likely that these effects contribute to changes in seizure threshold under these conditions.56,57,59 Indeed, withdrawal from neurosteroids can result in a lowered seizure threshold60, and an effect on tonic inhibition provides an attractive candidate mechanism to explain the menstrual variation in seizure frequency (catamenial epilepsy).61 In some conditions of chronic stress or during pregnancy, the effect of down-regulation of receptors mediating tonic inhibition is probably compensated by the increase in circulating neurosteroids directly enhancing the efficacy of remaining receptors.

Seizures themselves and epilepsy can also affect GABAA receptor-mediated inhibition. In particular, prolonged acute seizures alter GABAA receptor expression, and the epileptogenic process is accompanied by differential changes in subunits. During status epilepticus, there is an internalization of synaptic GABAA receptors62,63 providing a candidate mechanism for loss of benzodiazepine potency.64 However, extrasynaptic δ containing receptors are preserved.65 The efficacy of drugs that act on tonically active GABAA receptors, such as some anesthetic agents66,67, may therefore be maintained during status epilepticus. With the development of chronic temporal lobe epilepsy, animal models indicate that δ subunit expression decreases in dentate granule cells68 and α5 subunit expression decreases in CA1 pyramidal cells.69 Since these subunits contribute to tonic GABAA receptor currents in dentate granule cells and CA1 pyramidal cells, respectively, tonic inhibition in these cell types would be expected to decrease. Surprisingly, this is not the case: tonic currents are maintained or increased during epileptogenesis.28,30,70 This is not secondary to a decrease in GABA uptake, but is rather the result of the substitution of one set of extrasynaptic GABAA receptors by another and/or translocation of synaptic receptors to extrasynaptic sites. Although the tonic currents are preserved, their pharmacology changes because of the subunit alterations.28,30 What is perhaps more surprising is the maintenance of these tonic currents, even in the face of quite marked decreases in synaptic inhibition. The preservation of tonic currents is also evident in resected tissue from patients with refractory temporal lobe epilepsy.71

The network implications of the relative preservation of tonic, but loss of phasic, inhibition can only be speculated on, but are likely be similar to the effects observed when extracellular GABA increases: an increase in neuronal gain but a maintenance or increase in the offset of the input-output curve.37 The tonic current probably provides an adequate inhibitory restraint under conditions of low network activity, but as activity increases there may be two consequences: first inadequate fast compensatory changes through feed-forward and feed-back inhibition, and second increased neuronal gain resulting in larger numbers of firing neurons. This may provide the ideal conditions for seizure generation. This hypothesis could also explain why seizures are rare, intermittent events in people with even severe epilepsy.


Tonic currents are expressed in thalamocortical cells but not in reticular thalamic neurons.18,19 Such currents hyperpolarize thalamocortical neurons, and thus predispose to burst firing by de-inactivating T-type Ca2+ channels and/or activating the hyperpolarization-activated cation conductance. Tonic GABAA receptor signaling has therefore been proposed to be intimately involved in both the generation and pharmacology of absence seizures. Specifically, an increase in tonic currents in thalamocortical neurons results in neuronal hyperpolarization, and so a change of thalamocoritcal neuron firing from regular to burst patterns, promoting spike-wave generation. Several lines of evidence support this hypothesis.72,73 First, drugs that increase tonic currents in thalamocortical neurons promote absence seizures. This has been observed in animal models treated with GABA uptake inhibitors or with 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a drug that acts specifically on δ-containing receptors.74,75 Thalamocortical seizures, or their spike-wave EEG signature, have also been observed in humans in whom extracellular GABA concentrations have been increased by the administration of tiagabine, a GABA uptake inhibitors, or vigabatrin, a GABA transaminase inhibitor (both drugs used in therapy of partial epilepsy).76 Second, gamma-hydroxybutyrate (GHB), a drug that is well recognised to induce absence seizures, increases extracellular GABA in the thalamus.72,77 Third, δ subunit knockout mice are resistant to the pro-absence effects of such drugs.72 Fourth, increased tonic currents in thalamocortical neurons, and reduced GABA transporter activity, have been reported in animal models of spontaneous absence seizures (e.g. Genetic Absence Epilepsy Rat from Strasbourg - GAERS, lethargic mice, stargazer).72,73,78 Lastly, knockdown of the δ subunit in thalamocortical neurons in GAERS using antisense oligodeoxynucleotides inhibits absence seizures.72 It is also noteworthy that polymorphisms in δ subunits in humans have been associated with familial generalised epilepsies.79 However, interestingly these genetic variants tend to decrease GABAA receptor function and so how this change in tonic current contributes to the generation of absence seizures remains unclear.


There are two main approaches to target tonic inhibition: to target the specific GABAA receptor subtypes that mediate tonic inhibition, and to increase extracellular GABA concentrations.

α4δ containing receptors, which underlie tonic currents in dentate gyrus granule cells, are positively modulated by neurosteroids.16,53 In addition, they are particularly sensitive to anesthetic agents (such as propofol) and to THIP.20,66,67,80 Since these receptors are maintained in status epilepticus despite the internalization of γ-containing GABAA receptors, they could be a useful target in the later stages of status epilepticus when there is increasing benzodiazepine resistance. This may explain the usefulness of propofol as an anesthetic and anti-convulsant agent in the later stages of status epilepticus.81 Similarly, the preservation of tonic currents in partial epilepsy argues for the use of drugs that target these receptors. Ganaxalone, a synthetic neurosteroid, is one such drug;54 however, because the δ subunit is down-regulated by chronic exposure to neurosteroids, this approach may not be effective in the long term. δ subunit-containing receptors can also be directly activated by drugs such as THIP. A problem with this approach is lack of spatial specificity, in that such drugs target not only dentate granule cells but also thalamocortical neurons, thus inducing sleep and at higher concentrations anesthesia. In addition, as mentioned above, such drugs can have a pro-absence effect. Indeed, these drugs have been disappointing in animal seizure models.82

A further confounding factor when using GABAA receptor subtype specific drugs is that epileptogenesis results in subunit alterations that may decrease the efficacy of these compounds. This may be the case for the δ subunit in dentate gyrus granule cells (but see71) and also for the expression of the α5 subunit in hippocampal pyramidal cells.28

As for increases in extracellular GABA concentration, this can be achieved by inhibiting GABA transporters (tiagabine) or by decreasing GABA breakdown by GABA transaminase (vigabatrin). Another approach would be to increase GABA synthesis and it has been argued that some presently available antiepileptic drugs (e.g. valproate) may work partly via this mechanism83. Decreasing GABA uptake would seem an ideal approach to decreasing network excitability but this suffers from four important problems. First, although a specific inhibitor (for instance that targets GAT1) may be effective at increasing the tonic current in the hippocampus, this may not be the case in the neocortex where GAT3 can compensate for GAT1 inhibition.84 Second, as discussed above, increasing extracellular GABA will also have an effect on interneurons, so decreasing synaptic inhibition and paradoxically increasing network excitability.25 Third, increasing tonic inhibition in the thalamus can promote the generation of absence seizures.72 Fourth, increasing extracellular GABA also activates pre- and post-synaptic GABAB receptors and this can have complex network effects, both reducing excitability and synaptic inhibition (the latter by inhibiting vesicular GABA release).85 Lastly, reversal of GABA transporters during neuronal activity may even be a mechanism by which extracellular GABA can be increased during excessive neuronal activity.86 Thus, although tiagabine is an effective antiepileptic drug, it has been described to have, in some circumstances, pro-absence effects and its efficacy in humans is, overall, disappointing. Use of vigabatrin is also hampered by many of the same problems; its clinical use is also limited by concentric visual field restriction, which most likely results from GABA accumulation in the retina.87


Tonic currents have a profound effect on network excitability and are not lost in focal epilepsy. They therefore represent an attractive target for antiepileptic drug therapy. However, the hyperpolarization mediated by tonic currents in the thalamus may contribute to the generation of absence seizures. A promising area for future development is to target modulation of tonic currents in principal neurons, especially if the GABAA receptors subunits mediating them differ pharmacologically in the “epileptic” and healthy brain.


Farrant M, Nusser Z. Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors. Nat Rev Neurosci. 2005;6(3):215–229. [PubMed: 15738957]
Rossi DJ, Hamann M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity alpha6 subunit GABA(A) receptors and glomerular geometry. Neuron. 1998;20(4):783–795. [PubMed: 9581769]
Isaacson JS, Solís JM, Nicoll RA. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron. 1993;10(2):165–175. [PubMed: 7679913]
Semyanov A, Walker MC, Kullmann DM, Silver RA. Tonically active GABA A receptors: modulating gain and maintaining the tone. Trends Neurosci. 2004;27(5):262–269. [PubMed: 15111008]
Otis TS, Staley KJ, Mody I. Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release. Brain Res. 1991;545(1–2):142–150. [PubMed: 1650273]
Salin PA, Prince DA. Spontaneous GABAA receptor-mediated inhibitory currents in adult rat somatosensory cortex. J Neurophysiol. 1996;75(4):1573–1588. [PubMed: 8727397]
Wall MJ, Usowicz MM. Development of action potential-dependent and independent spontaneous GABAA receptor-mediated currents in granule cells of postnatal rat cerebellum. Eur J Neurosci. 1997;9(3):533–548. [PubMed: 9104595]
Brickley SG, Cull-Candy SG, Farrant M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors. J. Physiol. (Lond.) 1996;497(Pt 3):753–759. [PMC free article: PMC1160971] [PubMed: 9003560]
Rivera C, Voipio J, Kaila K. Two developmental switches in GABAergic signalling: the K+-Cl− cotransporter KCC2 and carbonic anhydrase CAVII. J. Physiol. (Lond.) 2005;562(Pt 1):27–36. [PMC free article: PMC1665491] [PubMed: 15528236]
Mehta AK, Ticku MK. An update on GABAA receptors. Brain Res Brain Res Rev. 1999;29(2–3):196–217. [PubMed: 10209232]
Lüscher B, Keller CA. Regulation of GABAA receptor trafficking, channel activity, and functional plasticity of inhibitory synapses. Pharmacol Ther. 2004;102(3):195–221. [PubMed: 15246246]
Walker MC. GABAA receptor subunit specificity: a tonic for the excited brain. J. Physiol. (Lond.) 2008;586(4):921–922. [PMC free article: PMC2375651] [PubMed: 18287385]
Wei W, Zhang N, Peng Z, Houser CR, Mody I. Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci. 2003;23(33):10650–10661. [PubMed: 14627650]
Overstreet LS, Westbrook GL. Synapse density regulates independence at unitary inhibitory synapses. J Neurosci. 2003;23(7):2618–2626. [PubMed: 12684447]
Nusser Z, Mody I. Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol. 2002;87(5):2624–2628. [PubMed: 11976398]
Stell BM, Brickley SG, Tang CY, Farrant M, Mody I. Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors. Proc Natl Acad Sci USA. 2003;100(24):14439–14444. [PMC free article: PMC283610] [PubMed: 14623958]
Stell BM, Mody I. Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons. J. Neurosci. 2002;22(10):RC223. [PubMed: 12006605]
Belelli D, Peden DR, Rosahl TW, Wafford KA, Lambert JJ. Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics. J Neurosci. 2005;25(50):11513–11520. [PubMed: 16354909]
Cope DW, Hughes SW, Crunelli V. GABAA receptor-mediated tonic inhibition in thalamic neurons. J Neurosci. 2005;25(50):11553–11563. [PubMed: 16354913]
Chandra D, Jia F, Liang J, et al. GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci USA. 2006;103(41):15230–15235. [PMC free article: PMC1578762] [PubMed: 17005728]
Hamann M, Rossi DJ, Attwell D. Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron. 2002;33(4):625–633. [PubMed: 11856535]
Caraiscos VB, Elliott EM, You-Ten KE, 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(10):3662–3667. [PMC free article: PMC373519] [PubMed: 14993607]
Wagner DA, Goldschen-Ohm MP, Hales TG, Jones MV. Kinetics and spontaneous open probability conferred by the epsilon subunit of the GABAA receptor. J Neurosci. 2005;25(45):10462–10468. [PubMed: 16280584]
Lindquist CEL, Birnir B. Graded response to GABA by native extrasynaptic GABA receptors. J Neurochem. 2006;97(5):1349–1356. [PubMed: 16573642]
Semyanov A, Walker MC, Kullmann DM. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat Neurosci. 2003;6(5):484–490. [PubMed: 12679782]
Mortensen M, Smart TG. Extrasynaptic alphabeta subunit GABAA receptors on rat hippocampal pyramidal neurons. J. Physiol. (Lond.) 2006;577(Pt 3):841–856. [PMC free article: PMC1890388] [PubMed: 17023503]
Glykys J, Mody I. Hippocampal network hyperactivity after selective reduction of tonic inhibition in GABA A receptor alpha5 subunit-deficient mice. J Neurophysiol. 2006;95(5):2796–2807. [PubMed: 16452257]
Scimemi A, Semyanov A, Sperk G, Kullmann DM, Walker MC. Multiple and plastic receptors mediate tonic GABAA receptor currents in the hippocampus. J Neurosci. 2005;25(43):10016–10024. [PubMed: 16251450]
Prenosil GA, Schneider Gasser EM, Rudolph U, et al. Specific subtypes of GABAA receptors mediate phasic and tonic forms of inhibition in hippocampal pyramidal neurons. J Neurophysiol. 2006;96(2):846–857. [PubMed: 16835366]
Zhang N, Wei W, Mody I, Houser CR. Altered localization of GABA(A) receptor subunits on dentate granule cell dendrites influences tonic and phasic inhibition in a mouse model of epilepsy. J Neurosci. 2007;27(28):7520–7531. [PubMed: 17626213]
Herd MB, Haythornthwaite AR, Rosahl TW, et al. The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J. Physiol. (Lond.) 2008;586(4):989–1004. [PMC free article: PMC2375644] [PubMed: 18079158]
Brickley SG, Revilla V, Cull-Candy SG, Wisden W, Farrant M. Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature. 2001;409(6816):88–92. [PubMed: 11343119]
LoTurco JJ, Owens DF, Heath MJ, Davis MB, Kriegstein AR. GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron. 1995;15(6):1287–1298. [PubMed: 8845153]
Demarque M, Represa A, Becq H, et al. Paracrine intercellular communication by a Ca2+- and SNARE-independent release of GABA and glutamate prior to synapse formation. Neuron. 2002;36(6):1051–1061. [PubMed: 12495621]
Ge S, Goh ELK, Sailor KA, et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature. 2006;439(7076):589–593. [PMC free article: PMC1420640] [PubMed: 16341203]
Mitchell SJ, Silver RA. Shunting inhibition modulates neuronal gain during synaptic excitation. Neuron. 2003;38(3):433–445. [PubMed: 12741990]
Pavlov I, Savtchenko LP, Kullmann DM, Semyanov A, Walker MC. Outwardly rectifying tonically active GABAA receptors in pyramidal cells modulate neuronal offset, not gain. J Neurosci. 2009;29(48):15341–15350. [PubMed: 19955387]
Chance FS, Abbott LF, Reyes AD. Gain modulation from background synaptic input. Neuron. 2002;35(4):773–782. [PubMed: 12194875]
Silver RA. Neuronal arithmetic. Nat Rev Neurosci. 2010;11(7):474–489. [PMC free article: PMC4750293] [PubMed: 20531421]
Martin LJ, Zurek AA, MacDonald JF, et al. Alpha5GABAA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory. J Neurosci. 2010;30(15):5269–5282. [PubMed: 20392949]
Dawson GR, Maubach KA, Collinson N, et al. An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther. 2006;316(3):1335–1345. [PubMed: 16326923]
Collinson N, Kuenzi FM, Jarolimek W, et al. Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosci. 2002;22(13):5572–5580. [PubMed: 12097508]
Atack JR, Bayley PJ, Seabrook GR, et al. L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors. Neuropharmacology. 2006;51(6):1023–1029. [PubMed: 17046030]
Ruiz A, Campanac E, Scott RS, Rusakov DA, Kullmann DM. Presynaptic GABAA receptors enhance transmission and LTP induction at hippocampal mossy fiber synapses. Nat Neurosci. 2010 Apr;13(4:):431–8. [PMC free article: PMC2898498] [PubMed: 20305647]
Bianchi L, Ballini C, Colivicchi MA, et al. Investigation on acetylcholine, aspartate, glutamate and GABA extracellular levels from ventral hippocampus during repeated exploratory activity in the rat. Neurochem Res. 2003;28(3–4):565–573. [PubMed: 12675146]
de Groote L, Linthorst ACE. Exposure to novelty and forced swimming evoke stressor-dependent changes in extracellular GABA in the rat hippocampus. Neuroscience. 2007;148(3):794–805. [PubMed: 17693036]
Ade KK, Janssen MJ, Ortinski PI, Vicini S. Differential tonic GABA conductances in striatal medium spiny neurons. J Neurosci. 2008;28(5):1185–1197. [PubMed: 18234896]
Janssen MJ, Ade KK, Fu Z, Vicini S. Dopamine modulation of GABA tonic conductance in striatal output neurons. J Neurosci. 2009;29(16):5116–5126. [PMC free article: PMC2707274] [PubMed: 19386907]
Overstreet LS, Westbrook GL. Paradoxical reduction of synaptic inhibition by vigabatrin. J Neurophysiol. 2001;86(2):596–603. [PubMed: 11495935]
Bai D, Zhu G, Pennefather P, et al. Distinct functional and pharmacological properties of tonic and quantal inhibitory postsynaptic currents mediated by gamma-aminobutyric acid(A) receptors in hippocampal neurons. Mol Pharmacol. 2001;59(4):814–824. [PubMed: 11259626]
Mann EO, Mody I. Control of hippocampal gamma oscillation frequency by tonic inhibition and excitation of interneurons. Nat Neurosci. 2010;13(2):205–12. [PMC free article: PMC2843436] [PubMed: 20023655]
Bianchi MT, Macdonald RL. Neurosteroids shift partial agonist activation of GABA(A) receptor channels from low- to high-efficacy gating patterns. J Neurosci. 2003;23(34):10934–10943. [PubMed: 14645489]
Belelli D, Herd MB. The contraceptive agent Provera enhances GABA(A) receptor-mediated inhibitory neurotransmission in the rat hippocampus: evidence for endogenous neurosteroids. J Neurosci. 2003;23(31):10013–10020. [PubMed: 14602815]
Bialer M, Johannessen SI, Levy RH, et al. Progress report on new antiepileptic drugs: a summary of the Tenth Eilat Conference (EILAT X), Epilepsy Res. 2–3. Vol. 92. 2010. pp. 89–124. [PubMed: 20970964]
Smith SS, Shen H, Gong QH, Zhou X. Neurosteroid regulation of GABAA receptors: Focus on the [alpha]4 and [delta] subunits. Pharmacology & Therapeutics. 2007;116(1):58–76. [PMC free article: PMC2657726] [PubMed: 17512983]
Maguire J, Mody I. Steroid hormone fluctuations and GABA(A)R plasticity. Psychoneuroendocrinology. 2009;34(Suppl 1):S84–90. [PMC free article: PMC3399241] [PubMed: 19632051]
Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005;8(6):797–804. [PubMed: 15895085]
Maguire J, Mody I. GABA(A)R plasticity during pregnancy: relevance to postpartum depression. Neuron. 2008;59(2):207–213. [PMC free article: PMC2875248] [PubMed: 18667149]
Maguire J, Mody I. Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci. 2007;27(9):2155–2162. [PubMed: 17329412]
Moran MH, Smith SS. Progesterone withdrawal I: pro-convulsant effects. Brain Res. 1998;807(1–2):84–90. [PubMed: 9757004]
Rogawski MA. Progesterone, neurosteroids, and the hormonal basis of catamenial epilepsy. Ann Neurol. 2003;53(3):288–291. [PubMed: 12601696]
Goodkin HP, Yeh J, Kapur J. Status epilepticus increases the intracellular accumulation of GABAA receptors. J Neurosci. 2005;25(23):5511–5520. [PMC free article: PMC2878479] [PubMed: 15944379]
Naylor DE, Liu H, Wasterlain CG. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci. 2005;25(34):7724–7733. [PubMed: 16120773]
Kapur J, Macdonald RL. Rapid seizure-induced reduction of benzodiazepine and Zn2+ sensitivity of hippocampal dentate granule cell GABAA receptors. J Neurosci. 1997;17(19):7532–7540. [PMC free article: PMC2892718] [PubMed: 9295398]
Goodkin HP, Joshi S, Mtchedlishvili Z, Brar J, Kapur J. Subunit-specific trafficking of GABA(A) receptors during status epilepticus. J Neurosci. 2008;28(10):2527–2538. [PMC free article: PMC2880323] [PubMed: 18322097]
McCartney MR, Deeb TZ, Henderson TN, Hales TG. Tonically active GABAA receptors in hippocampal pyramidal neurons exhibit constitutive GABA-independent gating. Mol Pharmacol. 2007;71(2):539–548. [PubMed: 17090706]
Caraiscos VB, Newell JG, You-Ten KE, et al. Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane. J Neurosci. 2004;24(39):8454–8458. [PubMed: 15456818]
Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the delta subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004;24(39):8629–8639. [PubMed: 15456836]
Houser CR, Esclapez M. Downregulation of the alpha5 subunit of the GABA(A) receptor in the pilocarpine model of temporal lobe epilepsy. Hippocampus. 2003;13(5):633–645. [PubMed: 12921352]
Zhan R, Nadler JV. Enhanced tonic GABA current in normotopic and hilar ectopic dentate granule cells after pilocarpine-induced status epilepticus. J Neurophysiol. 2009;102(2):670–681. [PMC free article: PMC2724337] [PubMed: 19474175]
Scimemi A, Andersson A, Heeroma JH, et al. Tonic GABA (A) receptor-mediated currents in human brain. Eur J Neurosci. 2006;24(4):1157–1160. [PubMed: 16930441]
Cope DW, Di Giovanni G, Fyson SJ, et al. Enhanced tonic GABAA inhibition in typical absence epilepsy. Nat Med. 2009;15(12):1392–1398. [PMC free article: PMC2824149] [PubMed: 19966779]
Belelli D, Harrison NL, Maguire J, et al. Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci. 2009;29(41):12757–12763. [PMC free article: PMC2784229] [PubMed: 19828786]
Coenen AML, Blezer EHM, van Luijtelaar ELJM. Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats. Epilepsy Research. 1995;21(2):89–94. [PubMed: 7588592]
Vergnes M, Marescaux C, Micheletti G, et al. Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci Lett. 1984;44(1):91–94. [PubMed: 6425742]
Genton P. When antiepileptic drugs aggravate epilepsy. Brain Dev. 2000;22(2):75–80. [PubMed: 10722956]
Williams SR, Turner JP, Crunelli V. Gamma-hydroxybutyrate promotes oscillatory activity of rat and cat thalamocortical neurons by a tonic GABAB, receptor-mediated hyperpolarization. Neuroscience. 1995;66(1):133–141. [PubMed: 7637863]
Richards DA, Lemos T, Whitton PS, Bowery NG. Extracellular GABA in the ventrolateral thalamus of rats exhibiting spontaneous absence epilepsy: a microdialysis study. J Neurochem. 1995;65(4):1674–1680. [PubMed: 7561864]
Dibbens LM, Feng H, Richards MC, et al. GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet. 2004;13(13):1315–1319. [PubMed: 15115768]
Bonin RP, Orser BA. GABA(A) receptor subtypes underlying general anesthesia. Pharmacol Biochem Behav. 2008;90(1):105–112. [PubMed: 18201756]
Holtkamp M, Tong X, Walker MC. Propofol in subanesthetic doses terminates status epilepticus in a rodent model. Ann Neurol. 2001;49(2):260–263. [PubMed: 11220748]
Löscher W, Schwark WS. Evaluation of different GABA receptor agonists in the kindled amygdala seizure model in rats. Exp Neurol. 1985;89(2):454–460. [PubMed: 2990987]
Kwan P, Sills GJ, Brodie MJ. The mechanisms of action of commonly used antiepileptic drugs. Pharmacology & Therapeutics. 2001;90(1):21–34. [PubMed: 11448723]
Keros S, Hablitz JJ. Subtype-specific GABA transporter antagonists synergistically modulate phasic and tonic GABAA conductances in rat neocortex. J Neurophysiol. 2005;94(3):2073–2085. [PubMed: 15987761]
Davies CH, Collingridge GL. The physiological regulation of synaptic inhibition by GABAB autoreceptors in rat hippocampus. J. Physiol. (Lond.) 1993;472:245–265. [PMC free article: PMC1160485] [PubMed: 8145143]
Richerson GB, Wu Y. Dynamic equilibrium of neurotransmitter transporters: not just for reuptake anymore. J Neurophysiol. 2003;90(3):1363–1374. [PubMed: 12966170]
Sills GJ, Patsalos PN, Butler E, et al. Visual field constriction: accumulation of vigabatrin but not tiagabine in the retina. Neurology. 2001;57(2):196–200. [PubMed: 11468302]
Copyright © 2012, Michael A Rogawski, Antonio V Delgado-Escueta, Jeffrey L Noebels, Massimo Avoli and Richard W Olsen.

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