The notion that drug treatments can improve memory performance has moved from the realm of science fiction to that of serious investigation. A popular working hypothesis is that cognition can be improved by altering the balance between excitatory and inhibitory neurotransmission. This review focuses on the unique physiological and pharmacological properties of GABAARs [GABA (γ-aminobutyric acid) subtype A receptors] that contain the α5 subunit (α5-GABAAR), as these receptors serve as candidate targets for memory-enhancing drugs.

Introduction

The GABAARs [GABA (γ-aminobutyric acid) subtype A receptors] belong to the cysteine-loop family of ligand-gated receptors, which also includes the nicotinic acetylcholine receptor, glycine receptor, glutamate-gated ion channel, zinc-gated ion channel and ionotropic serotonin receptor [1]. GABAARs are membrane-spanning proteins that surround a central pore to form an ion channel in the membrane. Each GABAAR is assembled as a pentamer from a pool of 19 different subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) [2]. The combination of subunits is specific, and the majority of native receptors in the mammalian brain contain α1, β2 and γ2 subunits in a 2:2:1 stoichiometry [3]. Distinct isoforms of GABAARs have different developmental, physiological and pharmacological properties and are localized to specific brain regions and subcellular compartments [4]. As we discuss below, GABAARs that contain the α5 subunit (α5-GABAARs) generate a tonic form of inhibition, are expressed mainly in extrasynaptic locations and play a role in modifying learning and memory behaviors.

Receptor distribution, function and pharmacology

The distribution of α5-GABAARs is relatively sparse and compartmentalized in the mammalian brain [5]. In total, approx. 5% of GABAARs contain the α5 subunit [6], although in the hippocampus, 20–25% of GABAARs contain this subunit [6]. The α5 subunit is predominantly localized to the stratum radiatum and stratum oriens of the CA1 and CA3 regions [5]. The distribution of the α5 subunit is also exceptionally high in the olfactory bulb [5], where 35% of neurons in the internal granule cell layer express α5-GABAARs [6]. The function of α5-GABAARs in this region remains unknown. Other regions that express the α5 subunit include the neocortex [7], subiculum [8] and substantia gelatinosa [9]; this subunit is also found in sympathetic preganglionic neurons [10].

Studies from our laboratory have shown that α5-GABAARs generate tonic inhibitory conductance in CA1 hippocampal pyramidal neurons [11]. This tonic conductance is significantly reduced in null mutant mice that have a genetic deletion of the gene that encodes the α5 subunit (Gabra5−/− mice); however, spontaneous synaptic GABAergic inhibition remains unchanged [11]. The tonic conductance is sensitive to midazolam [12], but not to zolpidem [11], which is consistent with the presence of α5 and γ subunits [13]. The α5-GABAARs display relatively high sensitivity to GABA, and they display slower desensitization kinetics than conventional synaptic GABAARs [11,14]. Accordingly, low ambient concentrations of GABA in the extracellular space are thought to activate a proportion of these receptors and generate tonic inhibitory conductance [15]. α5-GABAAR-generated tonic conductance has also been reported in cortical neurons [16], dopaminergic neurons of the striatum [17] and neurons in the intermediolateral cell column in spinal cord slices from rats [10]. Recombinant α5β3γ2 receptors have pharmacological properties similar to those of receptors that generate tonic current in CA1 hippocampal neurons [11,18], suggesting that this is the predominant combination of subunits in the hippocampus. Additionally, mass spectrometry identified that the α5 subunit associates with multiple α, β and γ subunits, but most frequently the β3 subunit [19].

Immunocytochemistry and in situ hybridization studies have indicated that α5-GABAARs are localized mainly, but not exclusively, to extrasynaptic regions of neurons [2022]. Immunogold staining of the hippocampus showed that α5-GABAARs were located on the dendrites of pyramidal neurons in the CA1 region of the rat hippocampus and cerebral cortex [23]. The clustering of α5-GABAARs is regulated by the binding of radixin, an actin-binding protein that anchors receptors to the cytoskeleton, to the activated form of the receptor [24].

The results of several electrophysiological studies suggest that α5-GABAARs also generate transient inhibitory synaptic potentials [2527]. In neocortical pyramidal cells, a proportion of synaptic GABAergic events are reduced by the α5-GABAAR-selective inverse agonist α5IA [28]. Inhibitory postsynaptic potentials generated by bistratified interneurons were potentiated by diazepam but not enhanced by zolpidem, which is consistent with an α5-GABAAR subtype [26]. Additionally, α5-GABAARs may contribute to synaptic GABAergic events with slow kinetics in cortical and hippocampal pyramidal neurons [27]. In hippocampal slices prepared from Gabra5−/− mice, the amplitude and decay time course of the evoked inhibitory postsynaptic currents were reduced, which suggests that deletion of α5-GABAARs may reduce synaptic inhibition [29]. In contrast, inhibiting α5-GABAARs with low concentrations of the benzodiazepine inverse agonist L-655,708 did not alter spontaneous IPSCs (inhibitory postsynaptic currents) in the CA1 and CA3 regions of the hippocampus, suggesting that spontaneous synaptic currents are not readily influenced by α5-GABAAR activity [11,30].

Finally, α5-GABAAR activity can reduce neuronal excitability by shunting mechanisms and/or changes in membrane potential [31]. In the hippocampus, α5-GABAAR activity reduces the excitability of individual pyramidal neurons [31] and networks of neurons [32] as well as the power of network oscillations [33]. The regulation of network excitability may contribute to α5-GABAAR regulation of hippocampus-dependent behavioural processes.

Learning, memory and α5-GABAARs

The concept that a decrease in GABAAR activity modifies learning and memory is not new, because it is well-recognized that bicuculline, a non-selective competitive antagonist of GABAARs, enhances memory performance [34]. Similarly, non-selective inverse agonists for the benzodiazepine site have been shown to enhance cognitive performance in animal models [35]. However, these drugs have anxiogenic, convulsant and proconvulsant properties that limit their clinical utility [35]. A key question is whether α5-GABAARs can be targeted by subtype-selective drugs to modulate memory without the adverse consequences of a global decrease in GABAergic inhibition.

Two mouse models, the Gabra5−/− mouse [29] and a point mutant (α5H105R) mouse with reduced expression of α5-GABAARs [22], have been used extensively to study the role of α5-GABAARs in cognition. Both types of mice have normal lifespans, breed normally and exhibit no overt compensatory change in other GABAAR subtypes. Initial studies showed that Gabra5−/− mice display enhanced acquisition in the matching-to-place version of the hippocampus-dependent water maze task [29], although this finding has not been replicated [36,37]. Furthermore, Gabra5−/− mice and α5H105R mutant mice show improved performance in the trace fear conditioning paradigm but perform similarly to wild-type mice in the non-hippocampus-dependent cued fear conditioning protocol [22,37].

A number of drugs have been developed that have a greater affinity for, or selective activity at, α5-GABAARs than for other GABAAR subtypes. These drugs include L-655,708, Ro15-4513, RY 080, RY 023 and RY 024 [38,39], which may improve memory with a relatively low occurrence of side effects [40]. Inverse agonists with selective binding or preferred efficacy for α5-GABAARs inhibit receptor activity allosterically via the benzodiazepine-binding site. The α5-GABAAR-function inverse agonist α5IA improves water maze learning and synaptic plasticity [41]. In vivo, this drug has no apparent convulsant, proconvulsant, or anxiogenic properties [41]. Furthermore, an analogue of α5IA, α5IA-II, regulates encoding and recall but not consolidation of spatial information [42]. The administration of α5IA-II either before training or immediately before memory-testing improved the performance of rats in the water maze, whereas α5IA-II injected following training had no effect. Administration of L-655,708 reduced the time required to find the platform in the Morris water maze and the amount of time spent in the correct quadrant during the probe trial [43].

Inhibitors of α5-GABAARs may be clinically important for the reversal of memory blockade induced by other drugs. For example, the general anesthetics etomidate [36] and isoflurane [44] robustly increase α5-GABAAR-mediated tonic conductance. This action probably contributes to the drugs' amnesic properties [36,45]. Notably, Gabra5−/− mice are resistant to the amnesic properties of etomidate [36], and L-655,708 prevents memory blockade by etomidate in wild-type mice [37]. In human volunteers, the memory-blocking effects of ethanol on the recall of word lists were reversed by α5IA-II [46], although the effects of α5IA-II alone on memory performance were not demonstrated. Furthermore, memory impairment caused by the muscarinic antagonist scopolamine can be reversed with BiRY-080, a novel inverse agonist with 130-fold selectivity for α5-GABAARs [47]. Inverse agonists including L-655,708 and α5IA are not currently available for clinical use; nevertheless, these drugs can serve as prototypes for drug development.

The molecular substrate for hippocampus-dependent learning and memory is thought to be the strengthening of synaptic connectivity, and brain slices have been used to study plasticity in hippocampal networks. LTP (long-term potentiation) of excitatory synaptic transmission in CA1 pyramidal neurons following stimulation of Schaffer collaterals is increased by non-selective inhibition of GABAARs [48]. Interestingly, hippocampal slices obtained from Gabra5−/− mice and α5H105R mice showed no differences in synaptic plasticity after high-frequency stimulation, despite enhanced memory behaviours [22,29]. In contrast, application of L-655,708 and α5IA to brain slices prepared from rats at a concentration that induces preferential binding to α5-GABAARs increased the LTP induced by theta burst stimulation [41,43]. These conflicting results suggest that, although α5-GABAARs may play an important role in the pharmacological enhancement of LTP, their role in baseline plasticity LTP may be smaller.

On a final note, although α5-GABAARs appear to play an important physiological role in the learning and memory process, these receptors may also contribute to pathological conditions, including ethanol addiction [49], schizophrenia [50], autism [51] and epilepsy [52]. Although there are major discrepancies that must still be addressed, α5-GABAARs will undoubtedly remain at the forefront of studies aimed at understanding the cellular basis of memory and the development of memory-modifying drugs.

Neuronal Glutamate and GABAA Receptor Function in Health and Disease: Biochemical Society Focused Meeting held at University of St Andrews, St Andrews, U.K., 21–24 July 2009. Organized and Edited by Chris Connolly and Jenni Harvey (Dundee, U.K.).

Abbreviations

     
  • GABA

    γ-aminobutyric acid

  •  
  • GABAAR

    GABA subtype A receptor

  •  
  • LTP

    long-term potentiation

Funding

This research was supported by operating grants from the Canadian Institutes of Health Research, Ottawa, Ontario, Canada [grant numbers MOP 79428 and MOP 38028 to B.A.O.], a Canada Research Chair Award in Anesthesia, Ottawa, Ontario, Canada (to B.A.O), Canadian Institutes of Health Research Canadian Graduate Scholarship, Ottawa, Ontario, Canada (to L.J.M.) and a Natural Sciences and Engineering Graduate Scholarship, Ottawa, Ontario, Canada (to R.P.B).

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