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Neural Plasticity
Volume 2012 (2012), Article ID 805830, 12 pages
http://dx.doi.org/10.1155/2012/805830
Review Article

GABA Metabolism and Transport: Effects on Synaptic Efficacy

Institute of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany

Received 14 November 2011; Accepted 19 December 2011

Academic Editor: Dirk Bucher

Copyright © 2012 Fabian C. Roth and Andreas Draguhn. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

GABAergic inhibition is an important regulator of excitability in neuronal networks. In addition, inhibitory synaptic signals contribute crucially to the organization of spatiotemporal patterns of network activity, especially during coherent oscillations. In order to maintain stable network states, the release of GABA by interneurons must be plastic in timing and amount. This homeostatic regulation is achieved by several pre- and postsynaptic mechanisms and is triggered by various activity-dependent local signals such as excitatory input or ambient levels of neurotransmitters. Here, we review findings on the availability of GABA for release at presynaptic terminals of interneurons. Presynaptic GABA content seems to be an important determinant of inhibitory efficacy and can be differentially regulated by changing synthesis, transport, and degradation of GABA or related molecules. We will discuss the functional impact of such regulations on neuronal network patterns and, finally, point towards pharmacological approaches targeting these processes.

1. Introduction

Activity within neuronal networks is contained between the extremes of complete silence and exceeding neuronal discharges. This general statement may seem intuitively right but has severe and nontrivial consequences for the function of neuronal networks. Several theoretical arguments and experimental findings support the notion that specific mechanisms secure a limited mean level of activity. Information content within neuronal networks is maximal under conditions of sparse coding, which means that only a minority of all local neurons is activated above threshold [1]. Furthermore, neurons are severely damaged by both extremes, that is, prolonged inactivity [25] or severe hyperactivity during epileptic seizures [6].

Many different mechanisms contribute to regulation of overall neuronal activity, including intrinsic neuronal properties [7, 8] and energy metabolism [9, 10]. At the core of homeostasis, however, is the interplay between synaptic excitation and inhibition (Figure 1). All neuronal circuits of higher animals contain excitatory and inhibitory transmitter systems forming intense feed-forward and feedback connections [11, 12]. The functional architecture of such networks can already explain homeostatic regulation of activity to a certain degree, and excitatory feedback loops tend to build up activity, which is counterbalanced by dampening actions of inhibitory feedback connections. A further element of cortical and subcortical microcircuits is inhibition of inhibitory neurons, resulting in a net excitation of downstream target cells. This mechanism may serve further functions in synchronizing neuronal activity and can be mediated by specialized interneurons [13]. In contrast, interactions between inhibitory neurons may also desynchronize neurons as, for example, Renshaw cells in the spinal cord [14, 15]. This mechanism may serve to reduce fatigue of muscle fibers.

805830.fig.001
Figure 1: Local inhibitory connections of cortical networks. Note the efferent and afferent connections indicated by arrows. In red, connections indicate glutamatergic excitation and blue connections GABAergic inhibition. Brown soma indicates an excitatory pyramidal cell (P), and blue-grey somata show inhibitory interneurons (INs). The left interneuron is integrated into a feedback inhibition loop, (FB) while the right interneuron shows feed-forward inhibition (FF). Differential targeting by the interneurons to the soma or dendrite points towards possible layer-specific actions of inhibition. Note that GABA released at the right synapse may, eventually, spill over to the neighbouring glutamatergic synapse. The global light blue staining indicates background GABA concentration that mediates tonic inhibition depending on local synaptic activity.

It should be noted that inhibitory neurons are not only important for balancing excitation. In several circuits, inhibitory neurons function as projection cells, rather than interneurons. For example, major projections within the basal ganglia and reticular nucleus of the thalamus and of the cerebellum are formed by GABAergic neurons [1618]. In such networks, activity-dependent modulation of inhibition may have specific effects beyond balancing excitation, for example, the generation of specific physiological or pathological oscillation pattern [19].

Homeostasis between excitation and inhibition cannot be reduced to a simple rule of network wiring. Recent evidence shows that inhibition has multiple specific functions within neuronal networks, far beyond a simple “break” [20, 21]. Moreover, inhibitory strength is not constant but must adapt to dynamically changing patterns and degrees of network activity. It does therefore not come as a surprise that recent work has elucidated multiple mechanisms of plasticity at inhibitory synapses [4, 2224]. An important subset of these mechanisms mediates homeostatic plasticity, that is, adaptation of inhibitory efficacy to the overall activity within a local network. Indeed, several lines of evidence suggest that GABAergic efficacy is upregulated in hyperactive networks [2529] and downregulated under conditions of reduced activity [5, 30, 31].

Such homeostatic reactions can, in principle, be mediated by multiple pre- and postsynaptic mechanisms. A particularly important regulatory system, however, is the concentration of the main mammalian inhibitory transmitter GABA (γ-aminobutyric acid). This paper shall summarize the molecular elements and functional mechanisms involved in regulation of GABA concentration within vesicles, cells, and in the extracellular space. We will quote experimental evidence indicating that GABA is homeostatically regulated during physiological and pathological changes of network activity. Finally, we will consider how molecular determinants of GABA concentration can be targeted by drugs for pharmacological therapy of neurological or psychiatric diseases.

2. Organization of GABAergic Synapses

In the mammalian CNS, inhibition is mediated by the amino acids GABA and glycine. The GABAergic system has been intensely explored during recent years and will therefore be the main focus of this paper. As a starting point, we will briefly summarize the main functional and structural elements of GABAergic synapses.

GABA binds to two different types of receptors-ion channels and metabotropic receptors. GABA-gated ion channels are selectively permeable for chloride and bicarbonate and have reversal potentials close to Cl equilibrium (ECl). These channels are mostly termed GABAA receptors, but a molecularly and pharmacologically distinguishable subset has also been termed GABAC receptors until recently, as discussed by Olsen and Seighart [32]. In most cases, the increase in chloride (and bicarbonate) conductance resulting from activation of ionotropic GABA receptors causes inhibition of the respective neuron, that is, decreased probability of action potential generation. This is easy to understand in cases where ECl is more negative than the membrane potential, such that opening of GABAA receptors causes hyperpolarisation and enhances the distance between membrane potential and action potential threshold. However, inhibition can also be mediated by more complex biophysical mechanisms, for example, shunting of the local membrane resistance, which can also counteract excitatory inputs. Even depolarizing actions of GABA can, in certain cases, be inhibitory [3335]. Conversely, excitatory actions of GABA may occur in specific situations, including early developmental stages [3639] and maladaptive processes, for example, in chronic epilepsy [40, 41]. The occurrence of depolarizing GABA responses under physiological conditions is presently subject to some controversy [39, 42]. receptors, in contrast, are members of the family of G-protein-coupled proteins [43] and react to GABA binding by dimerisation [44] and activation of downstream signal cascades. These include decreased probability of transmitter release and increase in pre- and postsynaptic K+ conductance [45, 46].

A complete survey of GABAergic mechanisms at the molecular, cellular, and network level is far beyond the scope of this paper. Rather, we will highlight three principles of organization of GABA-mediated inhibition that are particularly important for understanding how GABA regulates network activity. The molecular constituents involved in regulation of inhibitory strength are detailed below.(i)GABA regulates excitability on different temporal and spatial scales. One important mechanism is tonic inhibition, which results from diffusely distributed GABA within the extracellular space of networks, thereby reducing excitability of all local neurons (Figure 1). Recent evidence has shown that tonic inhibition is of major importance for reducing firing probability of defined types of neurons within cortical networks [24, 4749]. In some cells, this mechanism accounts for more than 50% of GABA-induced chloride conductance [50]. Background levels of GABA in neuronal tissue have been estimated to reach high-nanomolar to low-micromolar concentrations [51, 52]. In good accordance with this relatively low concentration, extrasynaptic GABA receptors have particularly high agonist affinity [47, 53, 54]. At the other extreme, phasic inhibition is mediated by locally and temporally restricted release of GABA from synaptic terminals. This action causes a short, exponentially rising and falling of the postsynaptic chloride conductance which can last from few to tens of milliseconds [50, 55]. Most GABAergic neurons seem to form such specific synaptic sites for phasic inhibition, but recent evidence indicates that there are also specialized interneurons which release GABA for tonic inhibition [5660]. Tonic inhibition depends on special GABA receptors, which can be selectively modulated by drugs, for example, neurosteroids. These specific receptor isoforms may be important in the pathophysiology of depression [61] and withdrawal symptoms [62]. Such examples of receptor heterogeneity may well open new therapeutic chances.(ii)GABAergic interneurons are diverse. Work on different networks has revealed an unprecedented multitude of different GABAergic neurons which are classified by their somatic location, dendritic branching, axonal projection, afferent synaptic integration, intrinsic membrane properties, and expression of molecular markers, especially neuromodulatory peptides and calcium-binding proteins. Extensive classification systems have been established for different circuits, for example, for the rodent neocortex [63, 64] and the hippocampus [13, 65]. Moreover, introducing the juxtacellular recording technique has enabled recordings from individual interneurons in behaving animals and subsequent in-depth structural analysis [66]. These data have shown that different types of interneurons are specialized to organize different patterns of network activity [67].(iii)In accordance with the heterogeneity and functional specialization of different cell types, experiments and computer modelling have revealed important functions of “inhibitory” interneurons in networks beyond merely dampening excitation. Interneurons turned out to play a key role in organizing the spatiotemporal activity of local networks, especially during synchronous network oscillations [6873]. Complementary neuroanatomical work has highlighted the structural basis for this function: interneurons have highly divergent axonal projections, cell type-specific afferent and efferent connectivity, and synchronizing mutual connections. All these properties favour synchronous rhythmic inhibition of large populations of principal cells [13, 69, 71, 7476]. It should be noted that the connections between excitatory projection cells and inhibitory interneurons provide an automatic homeostatic mechanisms at the network level. Feed forward or feedback inhibition is driven by excitatory inputs or outputs, respectively, from remote or local excitatory neurons. This mechanism does automatically recruit inhibitory neurons in an activity-dependent manner and, hence, balance local activity (Figure 1).

3. Key Molecules for GABAergic Signalling

The molecular organization of synapses is highly complex, and a complete review would be beyond the scope of this paper. We will restrict our remarks to some families of molecules that are crucial for understanding homeostatic regulation of GABA concentration (Figure 2).

805830.fig.002
Figure 2: Schematic drawing of transmitter release, transport, and synthesis at a GABAergic synaptic terminal. The axonal ending of an inhibitory interneuron (PRE) is drawn on the left, a glial cell (GLIA) on the right. Bottom structure indicates postsynaptic membrane of a target cell (POST), for example, a pyramidal neuron. Transporters are marked by flanking arrows, and synthesizing or degrading enzymes are marked by a centred arrow. Transporters are colour matched to substrates: GABA is shown as blue particles, glutamate in red, and glutamine in green. GS: glutamine synthetase, Mit: mitochondrion, PAG: phosphate-activated glutaminase, SV: synaptic vesicle, and V-ATPase: vacuolar-type H+-ATPase. For other abbreviations, see the main text.

Like many other neurotransmitters, GABA acts on ionotropic as well as metabotropic ion channels. GABAA receptors are pentameric ion channels composed out of a large variety of 19 homologous subunits [32, 77, 78]. Work during the past decades has elucidated numerous functional differences between molecular subtypes of GABAAR, including different expression patterns, differential modulation by benzodiazepines, neurosteroids and Zn2+, different compartmentalization within neurons, and different agonist affinity [32, 54, 79]. The latter properties are of special interest with respect to GABA concentration. GABAARs with low agonist affinity appear to be clustered at postsynaptic sites, whereas receptors with high affinity are mostly found extrasynaptically [47, 48]. The underlying sorting mechanisms are partially known and involve specific subsynaptic sorting signals within the gamma subunit and interactions with postsynaptic scaffolding proteins like gephyrin and collybistin [8083]. Extrasynaptic receptors, in contrast, are formed by subunits mediating high agonist affinity including α4, α6, and δ subunits [32, 47]. This distinction reflects the different concentrations of GABA at both sites: whereas synaptically released GABA may reach transient concentrations of ~1.5–3 mM [84, 85], extrasynaptic transmitter concentration has been estimated to lie in the low micromolar range of about 0.2–2.5 μM [47, 51, 52, 86]. As mentioned above, these apparently low “background” concentrations of GABA may be very efficient in regulating excitability [4750]. An additional distinct location of GABAA receptors is the presynaptic terminal itself. GABAergic auto- or heteroreceptors have been described at the axon terminals of various neurons, including spinal cord afferents [87], hippocampal mossy fibres [88], Schaffer collaterals [89], cerebellar interneurons [90], and pituitary terminals [91]. The effects of such receptors are diverse. Depending on the GABA-induced change in membrane potential and local membrane resistance, presynaptic GABAA receptors may increase or decrease transmitter release [92].

receptors, on the other hand, are G-protein-coupled transmembrane molecules which are activated by low concentrations of GABA and form dimers which then trigger secondary signalling cascades [4345]. At presynaptic terminals, activation of Rs reduces GABA release, forming the typical negative feedback loop of autoreceptor-mediated synaptic gain control. receptors are also present at glutamatergic terminals, pointing towards regular spillover of GABA from inhibitory to excitatory synapses (Figure 1, [47, 9395]). Postsynaptically, Rs hyperpolarize and inhibit neurons by activating inwardly rectifying KIR channels, giving rise to the “slow” or “late” phase of inhibition that follows fast, GABAAR-mediated effects and lasts several hundred milliseconds [96]. Furthermore, receptors can also mediate tonic inhibition, exerting negative control on overall network activity [97].

4. GABA Transport and Synthesis

While GABA receptors act as “detectors” of local GABA concentration, the regulation of GABA itself is achieved by several specialized molecular mechanisms mediating transport, sequestration, synthesis, and the degradation of GABA. We will briefly address each class of molecules involved in these processes.

Membrane-bound GABA transporters move GABA across the cell membrane (Figure 2). The direction and efficacy of this Na+-coupled transport results from the driving electrochemical gradient and is directed inwardly in most situations [98, 99]. However, upon strong depolarization or altered ion homeostasis, GABA transporters can also reverse direction. This mechanism leads to nonvesicular release of GABA which may be of special importance in pathophysiological situations [60, 100, 101]. GABA transporters appear in four different isoforms with affinities around 7 μM for rat GAT-1, 8 μM for rat GAT-2, 12 μM for rat GAT-3, and 93 μM for rat BGT-1 [102106]. Terminology of GABA transporters is not fully compatible between rats and mice [107]. In the following, we use the abbreviations for rat GABA transporters where ratGAT-1 = mouseGAT1; ratGAT-2 = mouse GAT3; ratGAT-3 = mouseGAT4; ratBGT-1 = mouse GAT2. GABA transporters are differentially expressed in the CNS. As a global rule, GAT-1 is the prevailing neuronal isoform in the rodent brain, and GAT-3 is strongly expressed in glial cells [108110]. Expression of different GAT isoforms is, however, overlapping, so that selective modulation of one isoform will always affect more than one cell type. It might therefore turn out impossible to achieve a strictly selective block of glial or neuronal GABA uptake with conventional pharmacological tools.

An alternative pathway for enriching GABA in presynaptic terminals is transmitter synthesis from glutamate. Similar to GAT-1/3, there are membrane-bound glutamate transporter molecules at presynaptic terminals of inhibitory interneurons, namely EAAC1 (also called EAAT3) [111113]. Moreover, neurons can synthesize glutamate from glutamine which can also be taken up by specialized transporters (see below) [114, 115]. GABAergic neurons express both mature isoforms of glutamate decarboxylase, GAD65 and GAD67 [116, 117], that convert the excitatory amino acid into GABA. The smaller isoform GAD65 is directly associated to presynaptic vesicles, indicating that glutamate, once present in the presynaptic cytosol, can be rapidly used for vesicular enrichment of GABA. Indeed, there are direct protein interactions between GAD65 and the vesicular GABA transporter VGAT (= VIAAT, vesicular inhibitory amino acid transporter), suggesting that conversion of glutamate into GABA and subsequent vesicular uptake of the transmitter may be strongly coupled processes [118].

More recently, glutamine has gained interest as an alternative source of GABA. The amino acid glutamine has long been known as the immediate precursor for glutamate. In the extracellular space, glutamine may reach concentrations of hundreds of μM [119, 120]. Enrichment of glutamate in excitatory central neurons involves uptake through specific glutamate transporters by glia cells, conversion into glutamine, export via “system N” glutamine transporters, uptake into neurons by “system A” glutamine transporters, and conversion into glutamate [121, 122]. There is increasing evidence for a similar role of this glutamate/glutamine cycle in GABA synthesis. Indeed, inhibitory interneurons in the hippocampus express the system A transporter SNAT1 [115], but not SNAT2 [123]. Recordings of epileptiform activity in rodent brain slices in vitro have revealed functional evidence for boosting of inhibition by glutamine via this mechanism [124127]. Using high-resolution recordings of miniature IPSCs in conjunction with pharmacological manipulation of glutamine levels and glutamine transport, these studies showed that glutamine can serve as a source for GABA, especially under conditions of increased synaptic activity. More recent evidence from rat hippocampal slices showed that the contribution of glutamine to vesicular GABA content is more pronounced in immature tissue, and that glutamine forms a constitutive source of vesicular GABA in immature hippocampal synapses on CA1 pyramidal cells. At later stages, the functional importance seems to be restricted to periods of enhanced synaptic activity [128]. This loss of function for constitutive GABA release under resting conditions goes along with an age-dependent decline in expression of SNAT1, both absolutely and in relation to the GABA-synthesizing enzyme GAD65.

5. Sequestration and Degradation of GABA

Within presynaptic terminals of GABAergic neurons, GABA is enriched in vesicles by the vesicular inhibitory amino acid transporter (VGAT = VIAAT). This protein is embedded in the vesicular membrane and uses the electrochemical gradient for H+ to shuffle GABA into small synaptic vesicles [129133]. Additionally, chloride gradients between vesicle lumen and presynaptic cytosol may contribute to the vesicular loading of GABA [129, 131]. Interestingly, VGAT processes both major mammalian inhibitory transmitters, GABA and glycine. This is a prerequisite for the observed GABAergic/glycinergic cotransmission by single vesicles in the spinal cord [134]. Modelling studies and biochemical data suggest that vesicular GABA uptake may achieve an~1000-fold increase of the transmitter in vesicles as compared to the presynaptic cytosol [135]. On the other side, recent evidence suggests that GABAergic synaptic vesicles are leaky, implying generation of a dynamic equilibrium between accumulation and loss of GABA, given that there is enough time to reach such a steady state [132, 136]. Taking this bidirectional transport into account, the “leaky bathtub” model of synaptic vesicles comes to rather low estimates of concentration gradients between cytosol and the inner vesicle space [132, 135, 137].

Finally, GABA and α-ketoglutarate can be transaminated, producing succinic semialdehyde and glutamate. The reaction is catalysed by GABA transaminase (GABA-T) which is present in mitochondria of glial cells and neurons [138140]. It is estimated that more than 90% of all GABA in the mammalian CNS is degraded in this way and contributes to energy metabolism in the tricarbonic acid cycle.

In summary, there are several different molecular pathways and compartments for enrichment, synthesis, and degradation of GABA (Figure 2). The resulting concentration of GABA in synaptic vesicles and in the extracellular space depends on the equilibrium between these mechanisms. It should be clearly stated that the absolute concentrations of GABA in the presynaptic cytosol, in vesicles, and in the extrasynaptic space are not known. The affinity constants of extrasynaptic GABA receptors may serve as a rough estimate of background concentrations (0.2–2.5 μM) [86]. Direct measurements from rat cerebrospinal fluid yielded similar or slightly higher values which may be lower in humans [141].

The highly dynamic time course of transmitter concentration in the synaptic cleft, on the other hand, has been estimated based on experimental and theoretical work in different types of neurons. Peak concentrations may be as high as 0.3 to 3 mM [85, 142147]. The cytosolic GABA concentration is most difficult to estimate or measure, especially since most of the neuronal GABA pool is used for energy metabolism rather than for synaptic inhibition.

It should be explicitly stated that none of the above-given numbers has been directly measured. Indeed, our knowledge on local GABA concentrations in different compartments is far from sufficient. This is even more concerning when we take into account the enormous heterogeneity of neurons [20, 63, 65], the different microarchitecture of different local circuits, and activity-dependent changes in GABA release and ionic homeostasis. A major challenge is the lack of quantitative data about key molecules and structures: How many GABA-uptake molecules are present at a given inhibitory synapse? What is their distribution with respect to the site of release? What is the precise extracellular volume at the synaptic cleft? How much GABA does go into glia cells and neurons, respectively? An important example for progress in this quantitative molecular approach to subcellular structure and function is the recent work on the vesicular proteasome by Takamori and colleagues [136].

6. Regulation of (GABA) in Physiology and Pathophysiology

Different lines of evidence support the view that the cellular and molecular mechanisms mentioned above make important contributions to homeostatic synaptic plasticity. This term covers changes of intrinsic and synaptic neuronal properties, which maintain the mean network activity within a determined range [4, 28]. Taking into consideration that network states change rapidly with changes in vigilance and behavioural state [148, 149], this is a nontrivial task. Individual neurons can change their activity at least by a factor of ~6 in different network patterns [150]. Nevertheless, under normal conditions, networks do neither fall into complete silence, nor into pathological hyperactivity.

Inhibition plays a critical role in network homeostasis. Most circuits contain specialized inhibitory cells which are activated by external afferent excitatory inputs (feedforward inhibition) or by collaterals from efferent excitatory axons (feedback inhibition) as illustrated in Figure 1 [11]. These inhibitory control loops ensure that excitatory neurons are inhibited in an activity-dependent manner. It should be noted, however, that inhibitory interneurons are much more than a “brake” or “gain control.” Recent evidence has revealed many other functions for these heterogeneous neurons: they are critical for organizing the complex spatial and temporal patterns of network oscillations [70, 71], selective gating of defined inputs or outputs [20], suppression of background activity [151], and precise timing of action potentials [67]. Corresponding with these specific functions, we are gaining increasing insight into the complexity of GABAergic signalling, diversity of interneurons, and plasticity of inhibitory synapses.

Notwithstanding these recent findings, however, inhibition does still have its traditional function, that is, limitation of neuronal activity. With respect to network homeostasis, this control function must adapt to changing degrees of activity in the local network. Several lines of evidence indicate that modulating GABA content of inhibitory interneurons is a key mechanism in this regulation process. For example, repetitive hyperactivity in the hippocampus of chronically epileptic rats causes upregulation of GADs, the key enzymes for production of GABA [29]. Conversely, the partial deafferentation of somatosensory cortex resulting from partial limb amputations leads to a downregulation of GABA, but not of GADs [30, 152]. These findings indicate that GABA levels are increased or decreased, respectively, in response to increasing or decreasing network activity. The underlying mechanisms are diverse with respect to time course and source of GABA.

Long-term changes in excitability, such as described above, require regulation of protein expression. Multiple studies from excitatory synapses show that changes in synaptic activity do indeed include lasting effects on protein synthesis and synaptic protein content [153, 154]. The underlying mechanisms involve calcium signalling in dendrites and nuclei [30, 155]. Much less is known about similar mechanisms in inhibitory interneurons. It would be of special importance to understand the activity-dependent regulation of key proteins such as GAD, VGAT, and others. Interestingly, BDNF (brain-derived neurotrophic factor) increases expression of GAD, indicating that neurotrophins are involved in inhibitory homeostatic plasticity. This would be well compatible with the general role of these molecules in activity-dependent plasticity [156]. Surprisingly, genes for inhibitory transmission can also be upregulated in excitatory, glutamatergic neurons following periods of enhanced activity. This intriguing finding suggests that excitatory neurons can adopt an active role in synaptic inhibition in certain situations. Such a “dual phenotype” has been clearly demonstrated in dentate granule cells, a major excitatory input cell type in the rodent hippocampus [157159]. The axons of granule cells, called mossy fibres, form strong glutamatergic synapses on proximal dendrites of CA3 pyramidal cells and do also contact inhibitory interneurons in this region (an example of feedforward inhibition). Upon strong repetitive stimulation or following epileptic seizures, mossy fibres start expressing proteins needed for the production and vesicular storage of GABA. Electrophysiological measurements show that this GABAergic phenotype is indeed functional, giving rise to mixed excitatory and inhibitory potentials in CA3 pyramids. The GABAergic phenotype of mossy fibres seems to be more pronounced in the juvenile brain [157], consistent with the general principle of enhanced plasticity in immature neurons. While the dual phenotype of granule cells may be an extreme example, several observations indicate that similar activity-dependent changes in expression of GABAergic molecules affect the vesicular pool of GABA in typical inhibitory interneurons. For example, expression of VGAT is altered following ischemia or excitotoxic stimulation [160162]. These changes go along with altered composition of the vesicular proteome, indicative of altered supply or release of GABAergic vesicles [163].

At a shorter time scale, GABA levels might be regulated by activity-dependent uptake of transmitter molecules. Experimental evidence for such changes came from direct injection of glutamate [164] or glutamine [124, 125] into hippocampal slices. Both approaches increased the amplitudes of miniature inhibitory postsynaptic currents (mIPSCs), indicating that the precursors had indeed been used to fuel the vesicular transmitter pool. Consistent with these findings, blocking membrane-bound transporters for glutamine, GABA, or glutamate can reduce the size of IPSCs [128, 162, 165, 166]. The relative contribution of GABA, glutamate, or glutamine uptake to the vesicular GABA pool remains, however, unknown. It can be expected that the contribution of different transmitter transporters differs among neuronal subtypes, brain regions, and developmental stages [128, 167]. However, due to the fast action of uptake molecules, it is well possible that homeostatic adaptations of intravesicular GABA concentration occur at time scales of few seconds. Strong activation of axons in the CA1 area of mouse hippocampal slices results in a rapid increase of mIPSC amplitudes, with onset time below 20 s. This increase is dependent on uptake of glutamate and GABA, indicating that increased extracellular transmitter concentrations in active neuronal networks automatically provide more “fuel” to the pool of releasable GABA, thereby constituting a negative feedback loop [165].

We have already discussed that tonic activation of GABA receptors by ambient transmitter concentrations provides a major mechanism for regulation of excitability [47, 48, 50]. It may, therefore, well be that changes in GABA uptake, production, and release cause altered tonic inhibition, possibly mediated by specialized subtypes of interneurons [56]. Quantitative knowledge about the contribution of these mechanisms is still lacking. It is also unclear how much nonvesicular release of GABA by reverse transport contributes to ambient GABA concentration. Situations of hyperactivity may favour such release mechanisms by sustained depolarization and altered local ion homeostasis [59, 60, 100, 168].

7. Pharmacological Use

Enhancing GABAergic inhibition is useful for the treatment of several pathological situations, including chronic pain, sleep disorders, anxiety, and—most importantly—epilepsy. In accordance with the principles outlined above, several drugs have been developed which alter presynaptic GABA content. One approach is blocking GABA degradation by GABA transaminase (GABA-T), using the suicide inhibitor γ-vinyl-GABA (GVG). Indeed, this drug does increase GABA levels in the brain [169, 170] and has anticonvulsant efficacy [171, 172]. Studies at the single cell level show that GVG increases miniature IPSC amplitude, consistent with a dynamic regulation of vesicular GABA concentration by the equilibrium between synthesis and degradation [173, 174]. Clinical use of GVG is, however, limited due to pathological changes of retinal cells and resulting scotoma [175].

An alternative approach suited to enhance synaptic GABA levels is the redirection of GABA uptake from glia to neurons. In glial cells, most GABA is degraded and fed into energy metabolism [176]. In contrast, neuronal GABA uptake can recycle the amino acid for use as a transmitter. It would therefore be ideal to have glia-specific GABA uptake inhibitors. Unfortunately, the molecular distinction between glial and neuronal GABA uptake is not strict, although there is some bias for GAT-1 in neurons and GAT-3 in glia [108110].

In summary, there is no doubt that changes in GABA concentration contribute significantly to network homeostasis in health and disease. More quantitative information about sources, compartmentalization, and local concentration of GABA is urgently needed, not at least in order to develop more specific drugs for reconstituting excitation-inhibition balance in pathological situations.

References

  1. J. Wolfe, A. R. Houweling, and M. Brecht, “Sparse and powerful cortical spikes,” Current Opinion in Neurobiology, vol. 20, no. 3, pp. 306–312, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. K. N. Hartman, S. K. Pal, J. Burrone, and V. N. Murthy, “Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons,” Nature Neuroscience, vol. 9, no. 5, pp. 642–649, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  3. E. Schonfeld-Dado and M. Segal, “Activity-dependent survival of neurons in culture: a model of slow neurodegeneration,” Journal of Neural Transmission, vol. 116, no. 11, pp. 1363–1369, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. A. Maffei and G. G. Turrigiano, “Multiple modes of network homeostasis in visual cortical layer 2/3,” Journal of Neuroscience, vol. 28, no. 17, pp. 4377–4384, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. V. Kilman, M. C. W. Van Rossum, and G. G. Turrigiano, “Activity deprivation reduces miniature IPSC amplitude by decreasing the number of postsynaptic GABAA receptors clustered at neocortical synapses,” Journal of Neuroscience, vol. 22, no. 4, pp. 1328–1337, 2002. View at Scopus
  6. Y. Ben-Ari, “Cell death and synaptic reorganizations produced by seizures,” Epilepsia, vol. 42, no. 3, pp. 5–7, 2001. View at Publisher · View at Google Scholar · View at Scopus
  7. J.P. Adelman, J. Maylie, and P. Sah, “Small-conductance Ca2+-activated K+ channels: form and function,” Annual Review of Physiology, vol. 74, pp. 245–269, 2012.
  8. A. Marty, “The physiological role of calcium-dependent channels,” Trends in Neurosciences, vol. 12, no. 11, pp. 420–424, 1989. View at Scopus
  9. M. O. Cunningham, D. D. Pervouchine, C. Racca et al., “Neuronal metabolism governs cortical network response state,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 14, pp. 5597–5601, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. C. Huchzermeyer, K. Albus, H. J. Gabriel et al., “Gamma oscillations and spontaneous network activity in the hippocampus are highly sensitive to decreases in pO2 and concomitant changes in mitochondrial redox state,” Journal of Neuroscience, vol. 28, no. 5, pp. 1153–1162, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. H. Mohler, P. Malherbe, A. Draguhn, and J. G. Richards, “GABAA-receptors: structural requirements and sites of gene expression in mammalian brain,” Neurochemical Research, vol. 15, no. 2, pp. 199–207, 1990. View at Scopus
  12. M. Ferrante, M. Migliore, and G. A. Ascoli, “Feed-forward inhibition as a buffer of the neuronal input-output relation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 42, pp. 18004–18009, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. T. F. Freund and G. Buzsáki, “Interneurons of the Hippocampus,” Hippocampus, vol. 6, no. 4, pp. 347–470, 1996. View at Scopus
  14. M. G. Maltenfort, C. J. Heckman, and W. Z. Rymer, “Decorrelating actions of renshaw interneurons on the firing of spinal motoneurons within a motor nucleus: a simulation study,” Journal of Neurophysiology, vol. 80, no. 1, pp. 309–323, 1998. View at Scopus
  15. F. J. Alvarez and R. E. W. Fyffe, “The continuing case for the Renshaw cell,” Journal of Physiology, vol. 584, no. 1, pp. 31–45, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. J. M. Tepper, C. J. Wilson, and T. Koós, “Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons,” Brain Research Reviews, vol. 58, no. 2, pp. 272–281, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. A. Gonzalo-Ruiz and A. R. Lieberman, “GABAergic projections from the thalamic reticular nucleus to the anteroventral and anterodorsal thalamic nuclei of the rat,” Journal of Chemical Neuroanatomy, vol. 9, no. 3, pp. 165–174, 1995. View at Publisher · View at Google Scholar · View at Scopus
  18. B. J. Fredette and E. Mugnaini, “The GABAergic cerebello-olivary projection in the rat,” Anatomy and Embryology, vol. 184, no. 3, pp. 225–243, 1991. View at Scopus
  19. A. Schnitzler and J. Gross, “Normal and pathological oscillatory communication in the brain,” Nature Reviews Neuroscience, vol. 6, no. 4, pp. 285–296, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  20. T. Klausberger and P. Somogyi, “Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations,” Science, vol. 321, no. 5885, pp. 53–57, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. G. Birke and A. Draguhn, “No simple brake the complex functions of inhibitory synapses,” Pharmacopsychiatry, vol. 43, no. 1, pp. S21–S31, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. L. Wang, A. Fontanini, and A. Maffei, “Visual experience modulates spatio-temporal dynamics of circuit activation,” Frontiers in Cellular Neuroscience, vol. 5, article 12, 2011.
  23. K. Lamsa, J. H. Heeroma, and D. M. Kullmann, “Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination,” Nature Neuroscience, vol. 8, no. 7, pp. 916–924, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. A. Semyanov, M. C. Walker, and D. M. Kullmann, “GABA uptake regulates cortical excitability via cell type-specific tonic inhibition,” Nature Neuroscience, vol. 6, no. 5, pp. 484–490, 2003. View at Scopus
  25. C. J. Wierenga and W. J. Wadman, “Miniature inhibitory postsynaptic currents in CA1 pyramidal neurons after kindling epileptogenesis,” Journal of Neurophysiology, vol. 82, no. 3, pp. 1352–1362, 1999. View at Scopus
  26. G. G. Turrigiano and S. B. Nelson, “Hebb and homeostasis in neuronal plasticity,” Current Opinion in Neurobiology, vol. 10, no. 3, pp. 358–364, 2000. View at Publisher · View at Google Scholar · View at Scopus
  27. G. G. Turrigiano and S. B. Nelson, “Homeostatic plasticity in the developing nervous system,” Nature Reviews Neuroscience, vol. 5, no. 2, pp. 97–107, 2004. View at Scopus
  28. G. G. Turrigiano, “Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same,” Trends in Neurosciences, vol. 22, no. 5, pp. 221–227, 1999. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Esclapez and C. R. Houser, “Up-regulation of GAD65 and GAD67 in remaining hippocampal GABA neurons in a model of temporal lobe epilepsy,” Journal of Comparative Neurology, vol. 412, no. 3, pp. 488–505, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. P. E. Garraghty, E. A. LaChica, and J. H. Kaas, “Injury-induced reorganization of somatosensory cortex is accompanied by reductions in GABA staining,” Somatosensory and Motor Research, vol. 8, no. 4, pp. 347–354, 1991. View at Scopus
  31. K. N. Hartman, S. K. Pal, J. Burrone, and V. N. Murthy, “Activity-dependent regulation of inhibitory synaptic transmission in hippocampal neurons,” Nature Neuroscience, vol. 9, no. 5, pp. 642–649, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. R. W. Olsen and W. Sieghart, “International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update,” Pharmacological Reviews, vol. 60, no. 3, pp. 243–260, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. J. S. Coombs, J. C. Eccles, and P. FATT, “The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential,” The Journal of physiology, vol. 130, no. 2, pp. 326–374, 1955. View at Scopus
  34. P. Rudomin and R. F. Schmidt, “Presynaptic inhibition in the vertebrate spinal cord revisited,” Experimental Brain Research, vol. 129, no. 1, pp. 1–37, 1999. View at Publisher · View at Google Scholar · View at Scopus
  35. G. Stuart, “Voltage-activated sodium channels amplify inhibition in neocortical pyramidal neurons,” Nature Neuroscience, vol. 2, no. 2, pp. 144–150, 1999. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. Y. Ben-Ari, E. Cherubini, R. Corradetti, and J. L. Gaiarsa, “Giant synaptic potentials in immature rat CA3 hippocampal neurones,” Journal of Physiology, vol. 416, pp. 303–325, 1989. View at Scopus
  37. Y. Ben-Ari, J. L. Gaiarsa, R. Tyzio, and R. Khazipov, “GABA: A pioneer transmitter that excites immature neurons and generates primitive oscillations,” Physiological Reviews, vol. 87, no. 4, pp. 1215–1284, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. E. Cherubini, J. L. Gaiarsa, and Y. Ben-Ari, “GABA: an excitatory transmitter in early postnatal life,” Trends in Neurosciences, vol. 14, no. 12, pp. 515–519, 1991. View at Publisher · View at Google Scholar · View at Scopus
  39. R. Tyzio, C. Allene, R. Nardou et al., “Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate,” Journal of Neuroscience, vol. 31, no. 1, pp. 34–45, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. Y. Ben-Ari and G. L. Holmes, “Effects of seizures on developmental processes in the immature brain,” Lancet Neurology, vol. 5, no. 12, pp. 1055–1063, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. G. Huberfeld, L. Wittner, S. Clemenceau et al., “Perturbed chloride homeostasis and GABAergic signaling in human temporal lobe epilepsy,” Journal of Neuroscience, vol. 27, no. 37, pp. 9866–9873, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. S. Rheims, C. D. Holmgren, G. Chazal et al., “GABA action in immature neocortical neurons directly depends on the availability of ketone bodies,” Journal of Neurochemistry, vol. 110, no. 4, pp. 1330–1338, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. K. Kaupmann, K. Huggel, J. Heid et al., “Expression cloning of GABAB receptors uncovers similarity to metabotropic glutamate receptors,” Nature, vol. 386, no. 6622, pp. 239–246, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. R. Kuner, G. Kohn, S. Grunewald, G. Eisenhardt, A. Bach, and H. C. Kornau, “Role of heteromer formation in GABAB receptor function,” Science, vol. 283, no. 5398, pp. 74–77, 1999. View at Publisher · View at Google Scholar · View at Scopus
  45. N. G. Bowery and D. A. Brown, “The cloning of GABAB receptors,” Nature, vol. 386, no. 6622, pp. 223–224, 1997. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  46. U. Misgeld, M. Bijak, and W. Jarolimek, “A physiological role for GABAB receptors and the effects of baclofen in the mammalian central nervous system,” Progress in Neurobiology, vol. 46, no. 4, pp. 423–462, 1995. View at Publisher · View at Google Scholar · View at Scopus
  47. I. Mody, “Distinguishing between GABAA receptors responsible for tonic and phasic conductances,” Neurochemical Research, vol. 26, no. 8-9, pp. 907–913, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. A. Semyanov, M. C. Walker, D. M. Kullmann, and R. A. Silver, “Tonically active GABAA receptors: modulating gain and maintaining the tone,” Trends in Neurosciences, vol. 27, no. 5, pp. 262–269, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  49. N. I. Holter, M. M. Zylla, N. Zuber, C. Bruehl, and A. Draguhn, “Tonic GABAergic control of mouse dentate granule cells during postnatal development,” European Journal of Neuroscience, vol. 32, no. 8, pp. 1300–1309, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. M. I. Banks and R. A. Pearce, “Kinetic differences between synaptic and extrasynaptic GABAA receptors in CA1 pyramidal cells,” Journal of Neuroscience, vol. 20, no. 3, pp. 937–948, 2000. View at Scopus
  51. U. Tossman, G. Jonsson, and U. Ungerstedt, “Regional distribution and extracellular levels of amino acids in rat central nervous system,” Acta Physiologica Scandinavica, vol. 127, no. 4, pp. 533–545, 1986. View at Scopus
  52. J. Lerma, A. S. Herranz, and O. Herreras, “In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis,” Brain Research, vol. 384, no. 1, pp. 145–155, 1986. View at Scopus
  53. N. Hájos, Z. Nusser, E. A. Rancz, T. F. Freund, and I. Mody, “Cell type- and synapse-specific variability in synaptic GABAA receptor occupancy,” European Journal of Neuroscience, vol. 12, no. 3, pp. 810–818, 2000. View at Publisher · View at Google Scholar · View at Scopus
  54. W. Hevers and H. Lüddens, “The diversity of GABAA receptors: pharmacological and electrophysiological properties of GABAA channel subtypes,” Molecular Neurobiology, vol. 18, no. 1, pp. 35–86, 1998. View at Scopus
  55. M. Bartos, I. Vida, M. Frotscher, J. R. P. Geiger, and P. Jonas, “Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network,” Journal of Neuroscience, vol. 21, no. 8, pp. 2687–2698, 2001. View at Scopus
  56. C. J. Price, B. Cauli, E. R. Kovacs et al., “Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area,” Journal of Neuroscience, vol. 25, no. 29, pp. 6775–6786, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. M. Capogna, “Neurogliaform cells and other interneurons of stratum lacunosum-moleculare gate entorhinal-hippocampal dialogue,” Journal of Physiology, vol. 589, no. 8, pp. 1875–1883, 2011. View at Publisher · View at Google Scholar · View at PubMed
  58. S. Oláh, M. Füle, G. Komlósi et al., “Regulation of cortical microcircuits by unitary GABA-mediated volume transmission,” Nature, vol. 461, no. 7268, pp. 1278–1281, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. S. M. Jones and M. J. Palmer, “Activation of the tonic GABAC receptor current in retinal bipolar cell terminals by nonvesicular GABA release,” Journal of Neurophysiology, vol. 102, no. 2, pp. 691–699, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. Y. Wu, W. Wang, A. Díez-Sampedro, and G. B. Richerson, “Nonvesicular inhibitory neurotransmission via reversal of the GABA transporter GAT-1,” Neuron, vol. 56, no. 5, pp. 851–865, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  61. A. Ströhle, E. Romeo, F. Di Michele et al., “GABAA receptor-modulating neuroactive steroid composition in patients with panic disorder before and during paroxetine treatment,” American Journal of Psychiatry, vol. 159, no. 1, pp. 145–147, 2002. View at Publisher · View at Google Scholar · View at Scopus
  62. J. Maguire and I. Mody, “Steroid hormone fluctuations and GABAAR plasticity,” Psychoneuroendocrinology, vol. 34, no. 1, pp. S84–S90, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. G. A. Ascoli, L. Alonso-Nanclares, S. A. Anderson et al., “Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex,” Nature Reviews Neuroscience, vol. 9, no. 7, pp. 557–568, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. H. Markram, M. Toledo-Rodriguez, Y. Wang, A. Gupta, G. Silberberg, and C. Wu, “Interneurons of the neocortical inhibitory system,” Nature Reviews Neuroscience, vol. 5, no. 10, pp. 793–807, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  65. P. Somogyi and T. Klausberger, “Defined types of cortical interneurone structure space and spike timing in the hippocampus,” Journal of Physiology, vol. 562, no. 1, pp. 9–26, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  66. D. Pinault, “A novel single-cell staining procedure performed in vivo under electrophysiological control: morpho-functional features of juxtacellularly labeled thalamic cells and other central neurons with biocytin or Neurobiotin,” Journal of Neuroscience Methods, vol. 65, no. 2, pp. 113–136, 1996. View at Publisher · View at Google Scholar · View at Scopus
  67. J. J. Tukker, P. Fuentealba, K. Hartwich, P. Somogyi, and T. Klausberger, “Cell type-specific tuning of hippocampal interneuron firing during gamma oscillations in vivo,” Journal of Neuroscience, vol. 27, no. 31, pp. 8184–8189, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. X. J. Wang and G. Buzsáki, “Gamma oscillation by synaptic inhibition in a hippocampal interneuronal network model,” Journal of Neuroscience, vol. 16, no. 20, pp. 6402–6413, 1996. View at Scopus
  69. R. D. Traub, M. O. Cunningham, T. Gloveli et al., “GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 19, pp. 11047–11052, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. M. A. Whittington, R. D. Traub, N. Kopell, B. Ermentrout, and E. H. Buhl, “Inhibition-based rhythms: experimental and mathematical observations on network dynamics,” International Journal of Psychophysiology, vol. 38, no. 3, pp. 315–336, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. E. O. Mann and O. Paulsen, “Role of GABAergic inhibition in hippocampal network oscillations,” Trends in Neurosciences, vol. 30, no. 7, pp. 343–349, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. E. O. Mann, J. M. Suckling, N. Hajos, S. A. Greenfield, and O. Paulsen, “Perisomatic feedback inhibition underlies cholinergically induced fast network oscillations in the rat hippocampus in vitro,” Neuron, vol. 45, no. 1, pp. 105–117, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. S. K. Towers, F. E. N. LeBeau, T. Gloveli, R. D. Traub, M. A. Whittington, and E. H. Buhl, “Fast network oscillations in the rat dentate gyrus in vitro,” Journal of Neurophysiology, vol. 87, no. 2, pp. 1165–1168, 2002. View at Scopus
  74. M. Blatow, A. Rozov, I. Katona et al., “A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex,” Neuron, vol. 38, no. 5, pp. 805–817, 2003. View at Publisher · View at Google Scholar · View at Scopus
  75. M. Bartos, I. Vida, M. Frotscher et al., “Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 20, pp. 13222–13227, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. S. R. Cobb, E. H. Buhl, K. Halasy, O. Paulsen, and P. Somogyl, “Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons,” Nature, vol. 378, no. 6552, pp. 75–78, 1995. View at Scopus
  77. E. A. Barnard, P. Skolnick, R. W. Olsen et al., “International union of pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function,” Pharmacological Reviews, vol. 50, no. 2, pp. 291–313, 1998. View at Scopus
  78. A. K. Mehta and M. K. Ticku, “An update on GABAA receptors,” Brain Research Reviews, vol. 29, no. 2-3, pp. 196–217, 1999. View at Publisher · View at Google Scholar · View at Scopus
  79. I. Mody and R. A. Pearce, “Diversity of inhibitory neurotransmission through GABAA receptors,” Trends in Neurosciences, vol. 27, no. 9, pp. 569–575, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  80. C. Essrich, M. Lorez, J. A. Benson, J. M. Fritschy, and B. Lüscher, “Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin,” Nature Neuroscience, vol. 1, no. 7, pp. 563–571, 1998. View at Scopus
  81. J. T. Kittler, K. McAinsh, and S. J. Moss, “Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission,” Molecular Neurobiology, vol. 26, no. 2-3, pp. 251–268, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  82. M. Giustetto, J. Kirsch, J. M. Fritschy, D. Cantino, and M. Sassoè-Pognetto, “Localization of the clustering protein gephyrin at GABAergic synapses in the main olfactory bulb of the rat,” Journal of Comparative Neurology, vol. 395, no. 2, pp. 231–244, 1998. View at Publisher · View at Google Scholar · View at Scopus
  83. M. Kneussel and H. Betz, “Clustering of inhibitory neurotransmitter receptors at developing postsynaptic sites: the membrane activation model,” Trends in Neurosciences, vol. 23, no. 9, pp. 429–435, 2000. View at Publisher · View at Google Scholar · View at Scopus
  84. J. W. Mozrzymas, E. D. Zarmowska, M. Pytel, and K. Mercik, “Modulation of GABAA receptors by hydrogen ions reveals synaptic GABA transient and a crucial role of the desensitization process,” Journal of Neuroscience, vol. 23, no. 22, pp. 7981–7992, 2003. View at Scopus
  85. A. Barberis, E. M. Petrini, and E. Cherubini, “Presynaptic source of quantal size variability at GABAergic synapses in rat hippocampal neurons in culture,” European Journal of Neuroscience, vol. 20, no. 7, pp. 1803–1810, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  86. J. Glykys and I. Mody, “The main source of ambient GABA responsible for tonic inhibition in the mouse hippocampus,” Journal of Physiology, vol. 582, no. 3, pp. 1163–1178, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  87. J. C. Eccles, R. F. Schmidt, and W. D. Willis, “Presynaptic inhibition of the spinal monosynaptic reflex pathway,” The Journal of physiology, vol. 161, pp. 282–297, 1962. View at Scopus
  88. H. Alle and J. R. P. Geiger, “GABAergic spill-over transmission onto hippocampal mossy fiber boutons,” Journal of Neuroscience, vol. 27, no. 4, pp. 942–950, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  89. S. F. Stasheff, D. D. Mott, and W. A. Wilson, “Axon terminal hyperexcitability associated with epileptogenesis in vitro. II. Pharmacological regulation by NMDA and GABAA receptors,” Journal of Neurophysiology, vol. 70, no. 3, pp. 976–984, 1993. View at Scopus
  90. B. M. Stell, P. Rostaing, A. Triller, and A. Marty, “Activation of presynaptic GABAA receptors induces glutamate release from parallel fiber synapses,” Journal of Neuroscience, vol. 27, no. 34, pp. 9022–9031, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  91. S. L. Hansen, B. Fjalland, and M. B. Jackson, “Modulation of GABAA receptors and neuropeptide secretion by the neurosteroid allopregnanolone in posterior and intermediate pituitary,” Pharmacology and Toxicology, vol. 93, no. 2, pp. 91–97, 2003. View at Publisher · View at Google Scholar
  92. A. Draguhn, N. Axmacher, and S. Kolbaev, “Presynaptic ionotropic GABA receptors,” Results and Problems in Cell Differentiation, vol. 44, pp. 69–85, 2007. View at Publisher · View at Google Scholar · View at PubMed
  93. D. M. Kullmann, “Spillover and synaptic cross talk mediated by glutamate and GABA in the mammalian brain,” Progress in Brain Research, vol. 125, pp. 339–351, 2000. View at Publisher · View at Google Scholar · View at Scopus
  94. M. Scanziani, “GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity,” Neuron, vol. 25, no. 3, pp. 673–681, 2000. View at Scopus
  95. K. E. Vogt and R. A. Nicoll, “Glutamate and γ-aminobutyric acid mediate a heterosynaptic depression at mossy fiber synapses in the hippocampus,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 3, pp. 1118–1122, 1999. View at Publisher · View at Google Scholar · View at Scopus
  96. J. S. Isaacson, J. M. Solis, and R. A. Nicoll, “Local and diffuse synaptic actions of GABA in the hippocampus,” Neuron, vol. 10, no. 2, pp. 165–175, 1993. View at Publisher · View at Google Scholar · View at Scopus
  97. Y. Wang, F. B. Neubauer, H. R. Lüscher, and K. Thurley, “GABAB receptor-dependent modulation of network activity in the rat prefrontal cortex in vitro,” European Journal of Neuroscience, vol. 31, no. 9, pp. 1582–1594, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  98. J. N. Cammack, S. V. Rakhilin, and E. A. Schwartz, “A GABA transporter operates asymmetrically and with variable stoichiometry,” Neuron, vol. 13, no. 4, pp. 949–960, 1994. View at Publisher · View at Google Scholar · View at Scopus
  99. J. L. Corey, J. Guastella, N. Davidson, and H. A. Lester, “GABA uptake and release by a mammalian cell line stably expressing a cloned rat brain GABA transporter,” Molecular membrane biology, vol. 11, no. 1, pp. 23–30, 1994. View at Scopus
  100. D. Attwell, B. Barbour, and M. Szatkowski, “Nonvesicular release of neurotransmitter,” Neuron, vol. 11, no. 3, pp. 401–407, 1993. View at Publisher · View at Google Scholar · View at Scopus
  101. M. J. During, K. M. Ryder, and D. D. Spencer, “Hippocampal GABA transporter function in temporal-lobe epilepsy,” Nature, vol. 376, no. 6536, pp. 174–177, 1995. View at Scopus
  102. A. Yamauchi, S. Uchida, H. M. Kwon et al., “Cloning of a Na+- and Cl--dependent betaine transporter that is regulated by hypertonicity,” Journal of Biological Chemistry, vol. 267, no. 1, pp. 649–652, 1992. View at Scopus
  103. J. Guastella, N. Nelson, H. Nelson et al., “Cloning and expression of a rat brain GABA transporter,” Science, vol. 249, no. 4974, pp. 1303–1306, 1990. View at Scopus
  104. B. I. Kanner and A. Bendahan, “Two pharmacologically distinct sodium- and chloride-coupled high-affinity γ-aminobutyric acid transporters are present in plasma membrane vesicles and reconstituted preparations from rat brain,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 7, pp. 2550–2554, 1990. View at Scopus
  105. Q. -R. Liu, B. Lopez-Corcuera, S. Mandiyan, H. Nelson, and N. Nelson, “Molecular characterization of four pharmacologically distinct gamma-aminobutyric acid transporters in mouse brain,” Journal of Biological Chemistry, vol. 268, no. 3, pp. 2106–2112, 1993.
  106. L. A. Borden, K. E. Smith, P. R. Hartig, T. A. Branchek, and R. L. Weinshank, “Molecular heterogeneity of the γ-aminobutyric acid (GABA) transport system. Cloning of two novel high affinity GABA transporters from rat brain,” Journal of Biological Chemistry, vol. 267, no. 29, pp. 21098–21104, 1992. View at Scopus
  107. A. Schousboe and H. S. Waagepetersen, “GABA: homeostatic and pharmacological aspects,” Progress in Brain Research, vol. 160, pp. 9–19, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  108. F. Conti, M. Melone, S. De Biasi, A. Minelli, N. C. Brecha, and A. Ducati, “Neuronal and glial localization of GAT-1, a high-affinity γ-aminobutyric acid plasma membrane transporter, in human cerebral cortex: with a note on its distribution in monkey cortex,” Journal of Comparative Neurology, vol. 396, no. 1, pp. 51–63, 1998. View at Publisher · View at Google Scholar
  109. A. Minelli, S. DeBiasi, N. C. Brecha, L. V. Zuccarello, and F. Conti, “GAT-3, a high-affinity GABA plasma membrane transporter, is localized to astrocytic processes, and it is not confined to the vicinity of GABAergic synapses in the cerebral cortex,” Journal of Neuroscience, vol. 16, no. 19, pp. 6255–6264, 1996. View at Scopus
  110. C. E. Ribak, W. M. Y. Tong, and N. C. Brecha, “GABA plasma membrane transporters, GAT-1 and GAT-3, display different distributions in the rat hippocampus,” Journal of Comparative Neurology, vol. 367, no. 4, pp. 595–606, 1996. View at Publisher · View at Google Scholar · View at Scopus
  111. J. D. Rothstein, L. Martin, A. I. Levey et al., “Localization of neuronal and glial glutamate transporters,” Neuron, vol. 13, no. 3, pp. 713–725, 1994. View at Publisher · View at Google Scholar · View at Scopus
  112. F. Conti, S. DeBiasi, A. Minelli, J. D. Rothstein, and M. Melone, “EAAC1, a high-affinity glutamate transporter, is localized to astrocytes and gabaergic neurons besides pyramidal cells in the rat cerebral cortex,” Cerebral Cortex, vol. 8, no. 2, pp. 108–116, 1998. View at Publisher · View at Google Scholar
  113. Y. He, W. G. M. Janssen, J. D. Rothstein, and J. H. Morrison, “Differential synaptic localization of the glutamate transporter EAAC1 and glutamate receptor subunit GluR2 in the rat hippocampus,” Journal of Comparative Neurology, vol. 418, no. 3, pp. 255–269, 2000. View at Publisher · View at Google Scholar · View at Scopus
  114. O. M. Larsson, J. Drejer, E. Kvamme, G. Svenneby, L. Hertz, and A. Schousboe, “Ontogenetic development of glutamate and GABA metabolizing enzymes in cultured cerebral cortex interneurons and in cerebral cortex in vivo,” International Journal of Developmental Neuroscience, vol. 3, no. 2, pp. 177–185, 1985. View at Scopus
  115. M. Melone, F. Quagliano, P. Barbaresi, H. Varoqui, J. D. Erickson, and F. Conti, “Localization of the glutamine transporter SNAT1 in rat cerebral cortex and neighboring structures, with a note on its localization in human cortex,” Cerebral Cortex, vol. 14, no. 5, pp. 562–574, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  116. M. G. Erlander and A. J. Tobin, “The structural and functional heterogeneity of glutamic acid decarboxylase: a review,” Neurochemical Research, vol. 16, no. 3, pp. 215–226, 1991. View at Scopus
  117. M. Esclapez, N. J. K. Tillakaratne, D. L. Kaufman, A. J. Tobin, and C. R. Houser, “Comparative localization of two forms of glutamic acid decarboxylase and their mRNAs in rat brain supports the concept of functional differences between the forms,” Journal of Neuroscience, vol. 14, no. 3, pp. 1834–1855, 1994. View at Scopus
  118. H. Jin, H. Wu, G. Osterhaus et al., “Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 4293–4298, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  119. I. Jacobson, M. Sandberg, and A. Hamberger, “Mass transfer in brain dialysis devices—a new method for the estimation of extracellular amino acids concentration,” Journal of Neuroscience Methods, vol. 15, no. 3, pp. 263–268, 1985. View at Scopus
  120. K. Kanamori and B. D. Ross, “Quantitative determination of extracellular glutamine concentration in rat brain, and its elevation in vivo by system A transport inhibitor, α-(methylamino)isobutyrate,” Journal of Neurochemistry, vol. 90, no. 1, pp. 203–210, 2004. View at Publisher · View at Google Scholar · View at PubMed
  121. L. K. Bak, A. Schousboe, and H. S. Waagepetersen, “The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer,” Journal of Neurochemistry, vol. 98, no. 3, pp. 641–653, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  122. S. Bröer and N. Brookes, “Transfer of glutamine between astrocytes and neurons,” Journal of Neurochemistry, vol. 77, no. 3, pp. 705–719, 2001. View at Publisher · View at Google Scholar · View at Scopus
  123. I. M. González-González, B. Cubelos, C. Giménez, and F. Zafra, “Immunohistochemical localization of the amino acid transporter SNAT2 in the rat brain,” Neuroscience, vol. 130, no. 1, pp. 61–73, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  124. S. L. Liang, G. C. Carlson, and D. A. Coulter, “Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1,” Journal of Neuroscience, vol. 26, no. 33, pp. 8537–8548, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  125. M. N. Fricke, D. M. Jones-Davis, and G. C. Mathews, “Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission,” Journal of Neurochemistry, vol. 102, no. 6, pp. 1895–1904, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  126. A. S. Bryant, B. Li, M. P. Beenhakker, and J. R. Huguenard, “Maintenance of thalamic epileptiform activity depends on the astrocytic glutamate-glutamine cycle,” Journal of Neurophysiology, vol. 102, no. 5, pp. 2880–2888, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  127. H. Tani, A. E. Bandrowski, I. Parada et al., “Modulation of epileptiform activity by glutamine and System A transport in a model of post-traumatic epilepsy,” Neurobiology of Disease, vol. 25, no. 2, pp. 230–238, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  128. M. N. Brown and G. C. Mathews, “Activity- and age-dependent modulation of GABAergic neurotransmission by System A-mediated glutamine uptake,” Journal of Neurochemistry, vol. 114, no. 3, pp. 909–920, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  129. G. Ahnert-Hilger and R. Jahn, “CLC-3 spices up GABAergic synaptic vesicles,” Nature Neuroscience, vol. 14, no. 4, pp. 405–407, 2011. View at Publisher · View at Google Scholar · View at PubMed
  130. C. C. Hsu, C. Thomas, W. Chen et al., “Role of synaptic vesicle proton gradient and protein phosphorylation on ATP-mediated activation of membrane-associated brain glutamate decarboxylase,” Journal of Biological Chemistry, vol. 274, no. 34, pp. 24366–24371, 1999. View at Publisher · View at Google Scholar · View at Scopus
  131. V. Riazanski, L. V. Deriy, P. D. Shevchenko, B. Le, E. A. Gomez, and D. J. Nelson, “Presynaptic CLC-3 determines quantal size of inhibitory transmission in the hippocampus,” Nature Neuroscience, vol. 14, no. 4, pp. 487–494, 2011. View at Publisher · View at Google Scholar · View at PubMed
  132. J. D. Erickson, S. De Gois, H. Varoqui, M. K. H. Schafer, and E. Weihe, “Activity-dependent regulation of vesicular glutamate and GABA transporters: a means to scale quantal size,” Neurochemistry International, vol. 48, no. 6-7, pp. 643–649, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  133. J. W. Hell, L. Edelmann, J. Hartinger, and R. Jahn, “Functional reconstitution of the γ-aminobutyric acid transporter from synaptic vesicles using artificial ion gradients,” Biochemistry, vol. 30, no. 51, pp. 11795–11800, 1991. View at Scopus
  134. P. Jonas, J. Bischofberger, and J. Sandkühler, “Corelease of two fast neurotransmitters at a central synapse,” Science, vol. 281, no. 5375, pp. 419–424, 1998. View at Publisher · View at Google Scholar · View at Scopus
  135. R. H. Edwards, “The neurotransmitter cycle and quantal size,” Neuron, vol. 55, no. 6, pp. 835–858, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  136. S. Takamori, M. Holt, K. Stenius et al., “Molecular anatomy of a trafficking organelle,” Cell, vol. 127, no. 4, pp. 831–846, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  137. J. Williams, “How does a vesicle know it is full?” Neuron, vol. 18, no. 5, pp. 683–686, 1997. View at Publisher · View at Google Scholar · View at Scopus
  138. M. J. Jung, B. Lippert, and B. W. Metcalf, “The effect of 4 amino hex 5 ynoic acid (γ acetylenic GABA, γ ethynyl GABA) a catalytic inhibitor of GABA transaminase, on brain GABA metabolism in vivo,” Journal of Neurochemistry, vol. 28, no. 4, pp. 717–723, 1977.
  139. I. Schousboe, B. Bro, and A. Schousboe, “Intramitochondrial localization of the 4 aminobutyrate 2 oxoglutarate transaminase from ox brain,” Biochemical Journal, vol. 162, no. 2, pp. 303–307, 1977. View at Scopus
  140. P. Kugler, “In situ measurements of enzyme activities in the brain,” Histochemical Journal, vol. 25, no. 5, pp. 329–338, 1993. View at Publisher · View at Google Scholar · View at Scopus
  141. J. A. Eckstein, G. M. Ammerman, J. M. Reveles, and B. L. Ackermann, “Analysis of glutamine, glutamate, pyroglutamate, and GABA in cerebrospinal fluid using ion pairing HPLC with positive electrospray LC/MS/MS,” Journal of Neuroscience Methods, vol. 171, no. 2, pp. 190–196, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  142. P. M. Burger, E. Mehl, P. L. Cameron et al., “Synaptic vesicles immunoisolated from rat cerebral cortex contain high levels of glutamate,” Neuron, vol. 3, no. 6, pp. 715–720, 1989. View at Scopus
  143. A. Barberis, E. M. Petrini, and J. W. Mozrzymas, “Impact of synaptic neurotransmitter concentration time course on the kinetics and pharmacological modulation of inhibitory synaptic currents,” Frontiers in Cellular Neuroscience, vol. 5, article 6, 2011.
  144. J. W. Mozrzymas, A. Barberis, K. Michalak, and E. Cherubini, “Chlorpromazine inhibits miniature GABAergic currents by reducing the binding and by increasing the unbinding rate of GABAA receptors,” Journal of Neuroscience, vol. 19, no. 7, pp. 2474–2488, 1999. View at Scopus
  145. M. V. Jones and G. L. Westbrook, “Desensitized states prolong GABAA channel responses to brief agonist pulses,” Neuron, vol. 15, no. 1, pp. 181–191, 1995. View at Scopus
  146. D. J. Maconochie, J. M. Zempel, and J. H. Steinbach, “How quickly can GABAA receptors open?” Neuron, vol. 12, no. 1, pp. 61–71, 1994. View at Scopus
  147. D. Perrais and N. Ropert, “Effect of zolpidem on miniature IPSCs and occupancy of postsynaptic GABAA receptors in central synapses,” Journal of Neuroscience, vol. 19, no. 2, pp. 578–588, 1999. View at Scopus
  148. G. Buzsáki, D. L. Buhl, K. D. Harris, J. Csicsvari, B. Czéh, and A. Morozov, “Hippocampal network patterns of activity in the mouse,” Neuroscience, vol. 116, no. 1, pp. 201–211, 2003. View at Publisher · View at Google Scholar · View at Scopus
  149. H. Berger, “Über das Elektrenkephalogramm des Menschen,” Archiv für Psychiatrie und Nervenkrankheiten, vol. 87, no. 1, pp. 527–570, 1929. View at Publisher · View at Google Scholar · View at Scopus
  150. J. Csicsvari, H. Hirase, A. Czurkó, A. Mamiya, and G. Buzsáki, “Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat,” Journal of Neuroscience, vol. 19, no. 1, pp. 274–287, 1999. View at Scopus
  151. F. Bähner, E. K. Weiss, G. Birke et al., “Cellular correlate of assembly formation in oscillating hippocampal networks in vitro,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 35, pp. E607–E616, 2011. View at Publisher · View at Google Scholar · View at PubMed
  152. L. A. Tremere and R. Pinaud, “Incongruent restoration of inhibitory transmission and general metabolic activity during reorganization of somatosensory cortex,” International Journal of Neuroscience, vol. 115, no. 7, pp. 1003–1015, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  153. M. Costa-Mattioli, W. S. Sossin, E. Klann, and N. Sonenberg, “Translational control of long-lasting synaptic plasticity and memory,” Neuron, vol. 61, no. 1, pp. 10–26, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  154. Y. Lu, K. Christian, and B. Lu, “BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory?” Neurobiology of Learning and Memory, vol. 89, no. 3, pp. 312–323, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  155. C. P. Bengtson, H. E. Freitag, J. M. Weislogel, and H. Bading, “Nuclear calcium sensors reveal that repetition of trains of synaptic stimuli boosts nuclear calcium signaling in CA1 pyramidal neurons,” Biophysical Journal, vol. 99, no. 12, pp. 4066–4077, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  156. J. M. Frade and Y. A. Barde, “Nerve growth factor: two receptors, multiple functions,” BioEssays, vol. 20, no. 2, pp. 137–145, 1998. View at Publisher · View at Google Scholar · View at Scopus
  157. R. Gutiérrez, “The dual glutamatergic-GABAergic phenotype of hippocampal granule cells,” Trends in Neurosciences, vol. 28, no. 6, pp. 297–303, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  158. G. Gómez-Lira, M. Lamas, H. Romo-Parra, and R. Gutiérrez, “Programmed and induced phenotype of the hippocampal granule cells,” Journal of Neuroscience, vol. 25, no. 30, pp. 6939–6946, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  159. M. C. Walker, A. Ruiz, and D. M. Kullmann, “Do mossy fibers release GABA?” Epilepsia, vol. 43, no. 5, pp. 196–202, 2002. View at Publisher · View at Google Scholar · View at Scopus
  160. J. R. Gomes, A. C. Lobo, C. V. Melo et al., “Cleavage of the vesicular GABA transporter under excitotoxic conditions is followed by accumulation of the truncated transporter in nonsynaptic sites,” Journal of Neuroscience, vol. 31, no. 12, pp. 4622–4635, 2011. View at Publisher · View at Google Scholar · View at PubMed
  161. M. Lamas, G. Gómez-Lira, and R. Gutiérrez, “Vesicular GABA transporter mRNA expression in the dentate gyrus and in mossy fiber synaptosomes,” Molecular Brain Research, vol. 93, no. 2, pp. 209–214, 2001. View at Publisher · View at Google Scholar · View at Scopus
  162. J. P. Sepkuty, A. S. Cohen, C. Eccles et al., “A neuronal glutamate transporter contributes to neurotransmitter GABA synthesis and epilepsy,” Journal of Neuroscience, vol. 22, no. 15, pp. 6372–6379, 2002. View at Scopus
  163. B. Hinz, A. Becher, D. Mitter et al., “Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain,” European Journal of Cell Biology, vol. 80, no. 10, pp. 615–619, 2001. View at Scopus
  164. G. C. Mathews and J. S. Diamond, “Neuronal glutamate uptake contributes to GABA synthesis and inhibitory synaptic strength,” Journal of Neuroscience, vol. 23, no. 6, pp. 2040–2048, 2003. View at Scopus
  165. K. Hartmann, C. Bruehl, T. Golovko, and A. Draguhn, “Fast homeostatic plasticity of inhibition via activity-dependent vesicular filling,” PLoS One, vol. 3, no. 8, Article ID e2979, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  166. K. Kirmse, A. Dvorzhak, S. Kirischuk, and R. Grantyn, “GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum,” Journal of Physiology, vol. 586, no. 23, pp. 5665–5678, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  167. A. Draguhn and U. Heinemann, “Different mechanisms regulate IPSC kinetics in early postnatal and juvenile hippocampal granule cells,” Journal of Neurophysiology, vol. 76, no. 6, pp. 3983–3993, 1996. View at Scopus
  168. S. Krause and W. Schwarz, “Identification and selective inhibition of the channel mode of the neuronal GABA transporter 1,” Molecular Pharmacology, vol. 68, no. 6, pp. 1728–1735, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  169. L. Gram, O. M. Larsson, A. H. Johnsen, and A. Schousboe, “Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons,” Epilepsy Research, vol. 2, no. 2, pp. 87–95, 1988. View at Scopus
  170. W. Loscher, R. Jackel, and F. Muller, “Anticonvulsant and proconvulsant effects of inhibitors of GABA degradation in the amygdala-kindling model,” European Journal of Pharmacology, vol. 163, no. 1, pp. 1–14, 1989. View at Scopus
  171. M. Bialer, S. I. Johannessen, H. J. Kupferberg, R. H. Levy, P. Loiseau, and E. Perucca, “Progress report on new antiepileptic drugs: a summary of The Fourth Eilat Conference (EILAT IV),” Epilepsy Research, vol. 34, no. 1, pp. 1–41, 1999. View at Publisher · View at Google Scholar · View at Scopus
  172. J. A. Cramer, R. Fisher, E. Ben-Menachem, J. French, and R. H. Mattson, “New antiepileptic drugs: comparison of key clinical trials,” Epilepsia, vol. 40, no. 5, pp. 590–600, 1999. View at Scopus
  173. D. Engel, I. Pahner, K. Schulze et al., “Plasticity of rat central inhibitory synapses through GABA metabolism,” Journal of Physiology, vol. 535, no. 2, pp. 473–482, 2001. View at Publisher · View at Google Scholar · View at Scopus
  174. N. Axmacher and A. Draguhn, “Inhibition of GABA release by presynaptic ionotropic GABA receptors in hippocampal CA3,” NeuroReport, vol. 15, no. 2, pp. 329–334, 2004. View at Publisher · View at Google Scholar · View at Scopus
  175. W. H. Butler, G. P. Ford, and J. W. Newberne, “A study of the effects of vigabatrin on the central nervous system and retina of Sprague Dawley and Lister-Hooded rats,” Toxicologic Pathology, vol. 15, no. 2, pp. 143–148, 1987.
  176. A. Schousboe, G. Svenneby, and L. Hertz, “Uptake and metabolism of glutamate in astrocytes cultured from dissociated mouse brain hemispheres,” Journal of Neurochemistry, vol. 29, no. 6, pp. 999–1005, 1977. View at Scopus