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Keywords:

  • anxiety;
  • memory;
  • schizophrenia;
  • sensory processing;
  • sleep

Abstract

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in regulating neuronal circuits and behavior. The pronounced diversity of GABAergic (γ-aminobutyric acid) interneurons is paralleled by an extensive diversity of GABAA receptor subtypes. The region- and domain-specific location of these receptor subtypes offers the opportunity to gain functional insights into the role of defined neuronal circuits. These developments are reviewed with regard to the regulation of sleep, anxiety, memory, sensorimotor processing and post-natal developmental plasticity.


Abbreviations used:
CCK

cholecystokinin

DMCM

methyl-6,7-dimethoxyl-4ethyl-beta-carboline-3-carboxylate

EEG

electroencephalogram

GABAergic

γ-aminobutyric acid

REM

rapid eye movement

Why GABA?

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

Due to their sophisticated cognitive abilities, mammals adapt to a rapidly changing environment. Evidence is accumulating that synchronous neuronal oscillations may underlie cognitive functions such as object perception, selective attention and working memory (Engel and Singer 2001; Buzsaki and Draguhn 2004) as well as consciousness (Llinás and Ribary 2001). Thus, in humans, on the macroscopic level, the analysis of high-frequency oscillatory activity such as the β (13–30 Hz) and γ (30–100 Hz) bands of the EEG (electroencephalogram) (McBain and Fisahn 2001; Whittington and Traub 2003; Bartos et al. 2007) may provide functional evidence for neuronal circuits in normal and diseased brain. A case in point is a recent high frequency EEG analysis of a visual perception task in normal controls and in schizophrenics (Spencer et al. 2004). Visual Gestalt stimuli elicited a γ-band oscillation generated in the visual cortex (Fig. 1). The fact that this oscillation was elicited by Gestalt patterns and was phase-locked to the reaction time suggests that it could reflect the neuronal mechanism involved in linking the elements of the illusory square into a coherent percept (Fig. 1). The occipital response-locked oscillation could be the most direct manifestation of visual feature-binding processes on the macroscopic EEG level. While both controls and schizophrenics display γ-band oscillations in visual Gestalt recognition, the frequency of the oscillation is lower in schizophrenics than in healthy individuals. This pattern may reflect an impairment of neural assemblies, which are thought to use γ-band oscillations as a mechanism for synchronization. This finding suggests that, although synchronization must occur for the perception of the Gestalt, it occurs at a lower frequency in schizophrenics. The neuronal networks are apparently not able to support high-frequency synchronization. If the disruption of fast neuronal oscillations indeed reflects a basic pathophysiological mechanism in schizophrenia, a deeper insight into the mechanisms of generation of these brain oscillations, together with a greater understanding of their functional role in information processing, may provide a background upon which to design and test new pharmacological therapeutic interventions in this and possibly other brain disorders (Whittington et al. 2000).

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Figure 1.  Perception and cognition indexed by neuronal synchrony. Stimulus-locked time-frequency maps of phase-locking values for controls and schizophrenia patients. Subjects fixated a central cross on a computer screen and responded with a button press according to whether an illusory square (far left) was present or absent (near left). The oscillation is thought to reflect the neuronal mechanism involved in linking the elements of the illusory square into a coherent percept. Color scales indicate phase-locking values (Spencer et al. 2004).

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The dynamics of neural networks is largely shaped by the activity pattern of interneurons, canonical elements in the generation of synchronous neural activity (Fig. 2). Most of these interneurons are GABAergic (γ-aminobutyric acid) (Buzsaki and Chrobak 1995; Freund and Buzsaki 1996; Paulsen and Moser 1998; Miles 2000; Klausberger et al. 2002, 2003; Markram et al. 2004; Mody and Pearce 2004) and their activity is thought to set the spatio-temporal conditions required for different patterns of network oscillations that may be critical for information processing (O’Keefe and Nadel 1978; O’Keefe and Recce 1993; Skaggs et al. 1996; Paulsen and Moser 1998; Engel et al. 2001; Harris et al. 2002; Metha et al. 2002;Traub et al. 2002; Klausberger et al. 2003; Gabernet et al. 2005). Thus, a deeper understanding of the GABAergic control of neuronal network oscillations may not only contribute deeper insights into the neural representation of cognitive functions in normal brain, but may also help restore the functionality of the diseased brain. However, the variety of inhibitory interneurons that are found in various circuits is daunting (Freund 2003; Markram et al. 2004). The diversity of GABAA receptors has therefore found increased attention in analyzing GABAergic control of behavior based on the genetic and pharmacological strategies as outlined below.

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Figure 2.  Feed forward and feedback inhibition. Canonical circuits of GABAergic interneurons in feed forward (left) and feed back inhibition (right). Pyr, pyramidal cell.

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Diversity of interneurons

To achieve a strict time control of principal cells, GABAergic interneurons display several remarkable features. (i) Their action potential is traditionally faster than that of pyramidal cells and the kinetics of synaptic events that excite inhibitory cells are faster than those that excite pyramidal cells (Geiger et al. 1997; Martina et al. 1998). (ii) The GABAergic interneurons are morphologically highly diverse, which reflects their multiple functions in neuronal networks (Gupta et al. 2000; Markram et al. 2004). (iii) The interneurons show a domain-specific innervation of principal cells (Fig. 3). Depending on the type of interneuron, particular input domains of pyramidal cells can be selectively regulated. The output of pyramidal cells can be specifically regulated by axo-axonic GABAergic interneurons. (iv) The response properties of interneuron signalling are influenced by the type of GABAA receptor expressed synaptically or extrasynaptically. For instance, the soma of hippocampal pyramidal cells is innervated by two types of basket cells. The fast-spiking parvalbumin-containing basket cells form synapses containing α1GABAA receptors, which display fast kinetics of deactivation (Nyíri et al. 2001,Klausberger et al. 2002; Freund and Buzsaki 1996; Pawelzik et al. 2002; Mody and Pearce 2004). In contrast, the synapses of the regular-spiking cyolecystokinin (CCK)-positive basket cells contain α2GABAA receptors, which display slower kinetics than α1 receptors (Nyíri et al. 2001;Brussaard and Herbison 2000; Hutcheon et al. 2000; Jüttner et al. 2001; Vicini et al. 2001). Axon initial segments of principal cells also contain α2 receptors which appear to be kinetically sufficient for simple on/off signalling. Furthermore, distinct GABAA receptors are segregated to synaptic and extrasynaptic membranes (Nusser et al. 1998; Fritschy and Brünig 2003). Thus, functionally specialized interneurons operate with the kinetically appropriate GABAA receptor subtypes to regulate network behavior (Figs 1 and 2). As GABAergic interneurons are operative throughout the brain, a highly diverse repertoire of GABAA receptors is required. GABAA receptor subtypes were therefore investigated as molecular markers for particular circuits and as determinants for specific brain functions.

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Figure 3.  Domain-specific distribution of GABAA receptor subtypes on a hippocampal pyramidal cell dendrite. The excitatory input at the spines and the GABAergic input are depicted. Synaptic α2- or α3-subunits are located opposite a GABA-releasing pre-synaptic terminal. By contrast, GABAA receptors containing the α5-subunit are located extrasynaptically at the base of the spines, which receive excitatory glutamatergic input via NMDA receptors. Thus, GABAA receptors containing the α5-subunit are strategically located to modulate the processing of the excitatory input.

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Multiplicity of distinct GABAA receptors

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

Based on the presence of seven subunit families comprising at least 18 subunits in the central nervous system (α1–6, β1–3, γ1–3, δ, ɛ, θ, ρ1–3,), the GABAA-receptors display an extraordinary structural heterogeneity. Most GABAA receptors subtypes in vivo are considered to be heteropentamers composed of isoforms of α, β and γ subunits (Fig. 4; for review see Barnard et al. 1998; Whiting et al. 2000; Sieghart and Sperk 2002; Möhler et al. 2000, 2005; Möhler 2001, 2002, 2006; Fritschy et al. 2004; Rudolph and Möhler 2006; Sieghart 2006). The structural diversity of GABAA receptors provides receptors which differ in their channel kinetics, affinity for GABA, rate of desensitization, ability for transient chemical modification such as phosphorylation, cell-type-specific expression and – in case of multiple receptors in a neuron – a domain-specific location (Mody and Pearce 2004).

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Figure 4.  Scheme of GABAergic synapse depicting major elements of signal transduction. The GABAA receptors are heteromeric membrane proteins which are linked by a yet unknown mechanism to the synaptic anchoring protein gephyrin and the cytoskeleton. The sequence of subunits corresponds to a modeling proposal (Ernst et al. 2003). The binding sites for GABA and benzodiazepines are located at the interface of α/β and α/γ2 subunits, respectively. Synaptic GABAA receptors mediate phasic inhibition providing a rapid point-to-point communication for synaptic integration and control of rhythmic network activities. Extrasynaptic GABAA receptors (not shown) are activated from synaptic spillover or non-vesicular release of GABA. By mediating tonic inhibition, they provide a maintenance level of reduction in neuronal excitability (Mody and Pearce 2004; Möhler et al. 2005).

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Diazepam-sensitive GABAA receptors

Receptors containing the α1, α2, α3 or α5 subunits in combination with any of the β subunits and the γ2 subunit are most prevalent in the brain (Table 1). These receptors are sensitive to benzodiazepine modulation with the drug-binding site located at the interface between the α and the γ2 subunit. The major receptor subtype is assembled from the subunits α1β2γ2, with only a few brain regions lacking this receptor (e.g. granule cell layer of the olfactory bulb, reticular nucleus of the thalamus, spinal cord motoneurons) (Fritschy and Möhler 1995;Pirker et al. 2000; Fritschy and Brünig 2003).

Table 1.   GABAA receptor subtypes*
SubunitsLocalizationPharmacology
  1. *For details see text and ref. (Möhler et al. 2002; Fritschy and Brünig 2003; Wallner et al. 2006). The term benzodiazepine refers to diazepam and structurally related agents in clinical use. The % values are estimates taking all brain GABAA receptors as 100%.

α1β2γ2Major subtype (60%). Synaptic and extrasynapticBenzodiazepine-sensitive. Mediates sedative and anti-convulsant activity
α2β3γ2Minor subtype (15–20%). SynapticBenzodiazepine-sensitive. Mediates anxiolytic activity
α3βnγ2Minor subtype (10–15%)Benzodiazepine-sensitive. Pharmacology yet unclear
α5β1,3γ2<5% of receptors. Extrasynaptic (cerebral cortex, hippocampus, olf. bulb)Benzodiazepine-sensitive. Mediates modulation of temporal and spatial memory
α4βnδ<5% of receptors. ExtrasynapticInsensitive to benzodiazepines. Sensitive to low concentration of ethanol
α4βnγ<5% of receptors. ExtrasynapticInsensitive to benzodiazepines
α6βnδSmall population. Extrasynaptic (only in cerebellum)Insensitive to benzodiazepines. Sensitive to low concentration of ethanol
α6β2,3γ2<5% of receptors. Synaptic (only in cerebellum)Insensitive to benzodiazepines

Receptors containing the α2 or α3 subunit are considerably less abundant and are highly expressed in brain areas where the α1 subunit is absent or present at low levels. The α2 and α3 subunits are frequently co-expressed with the β3 and γ2 subunits, which are particularly evident in hippocampal pyramidal neurons (α2β3γ2) and in cholinergic neurons of the basal forebrain (α3β3γ2). The α3 GABAA receptors are the main subtypes expressed in monoaminergic and basal forebrain cholinergic cells (Gao et al. 1993) and are, in addition, strategically located in the thalamic reticular nucleus for modulating the thalamic oscillations (Huntsmann et al. 1999; Sohal et al. 2003). Marked differences in desensitization kinetics have been reported between synaptic α2- and extrasynaptic α3-receptors (α2β2,3γ2 vs. α3β2,3γ2), whereby the latter desensitize very slowly as shown in olivary nucleus neurons (Devor et al. 2001); the factors regulating GABAA receptor kinetics at synaptic and extrasynaptic sites are yet unknown (Moss and Smart 2001). The ligand-binding profile of the α2- and α3-receptors differs from that of α1β2γ2 by having a considerably lower displacing potency for ligands such as βCCM, CL 218 872, and zolpidem (Möhler et al. 1996).

Receptors containing the α5 subunit are of minor abundance in the brain but are expressed to a significant extent in the hippocampus, where they comprise 15–20% of the diazepam-sensitive GABAA receptor population, predominately co-assembled with the β3 and γ2 subunits. Pharmacologically, the α5-receptors are differentiated from α1β2γ2, α2β3γ2 and α3β3γ2 receptors by a lower affinity for CL 218, 872 and near-insensitivity to zolpidem (Möhler et al. 1996.

The subunits γ1 and γ3 characterize a small population of receptors that contain various types of α and β subunits. Because of their reduced affinity for the classical benzodiazepines, they do not appear to contribute to any great extent to their pharmacology in vivo.

It should be kept in mind that complex benzodiazepine actions such as the development of tolerance can implicate more than a single receptor subtype. For instance, while the sedative action of diazepam is mediated by α1 GABAA receptors (see below), the development of tolerance to this action under chronic diazepam treatment requires the interaction with both α1 GABAA receptors and α5 GABAA receptors (van Rijnsoever et al. 2004).

Diazepam-insensitive GABAA receptors

GABAA receptors that do not respond to clinically used ligands such as diazepam, flunitrazepam, clonazepam and zolpidem are of low abundance in the brain and are largely characterized by the α4 and α6 subunits (Table 1). Receptors containing the α4 subunit are generally expressed at very low abundance but more prominently in thalamus and dentate gyrus (Pirker et al. 2000); those containing the α6 subunit are restricted to the granule cell layer of the cerebellum (30–50% of all GABAA receptors in the cerebellum; Nusser et al. 1996; Pöltl et al. 2003). Both receptor populations are structurally heterogeneous, and the majority of the α6-containing receptors are of the α6β2γ2 combination. Apart form the lack of affinity of classical benzodiazepines, the benzodiazepine-site profile of α4 and α6 receptors is characterized by a low affinity for flumazenil and bretazenil and an agonistic efficacy of Ro 15–4513 and bretazenil (Benson et al. 1998). In addition to the γ2 subunit, the δ subunit is frequently co-assembled with the α4 or the α6 subunit in benzodiazepine-insensitive receptors (Möhler et al. 2000; Whiting et al. 2000; Möhler 2001). Receptors containing the δ subunit are located exclusively at extrasynaptic sites as shown in dentate gyrus and cerebellum. They are tailor-made for tonic inhibition, because of their high affinity for GABA and slow desensitization kinetics (Brickley et al. 1996; Mody and Pearce 2004;Brickley et al. 2001).

In the retina, homomeric receptors consisting of the ρ subunit represent a particular class of GABA-gated chloride channels, which are insensitive to bicuculline and not modulated by barbiturates or benzodiazepines. Because of these distinctive features, the receptors were originally termed GABAc-receptors (Bormann 2000), although they are a homomeric class of GABAA-receptors (Barnard et al. 1998).

Pharmacology of GABAA receptor subtypes

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

Benzodiazepines remain among the most widely prescribed drugs used mainly in the treatment of sleep disturbances, anxiety disorders, restlessness, muscle tension, status epilepticus and as co-medication in anesthesia. While classical benzodiazepines interact equally with all GABAA receptor subtypes, drugs with selectivity for particular receptor subtypes were expected to provide more selective therapy with fewer side effects. The pharmacological relevance of GABAA receptor subtypes for the spectrum of benzodiazepine effects was recently identified based on a genetic approach (Rudolph et al. 1999, 2001; Löw et al. 2000; McKernan et al. 2000; Whiting et al. 2000; Möhler 2002; Möhler et al. 2002; Whiting 2003a). Experimentally, the GABAA receptor subtypes were rendered diazepam-insensitive by replacing a conserved histidine residue in the drug-binding site with an arginine residue in each of the respective α subunit genes [α1(H101R), α2(H101R), α3(H126R) and α5(H105R)] (Rudolph et al. 1999; Löw et al. 2000). The behavioral analysis of these mutant strains permitted the allocation of the benzodiazepine drug actions to the distinct α1-, α2-, α3- or α5-GABAA-receptor subtypes (Rudolph et al. 1999, 2001; Löw et al. 2000; Crestani et al. 2002). In addition, by means of their distinct expression patterns, the particular GABAA receptor subtype identifies the neuronal networks, which mediated the respective behaviors.

Receptors for sleep

The sedative component of benzodiazepines, measured by the reduction of locomotor activity, is attributed to neuronal circuits expressing α1GABAA receptors, the most prevalent receptor subtype in the brain. Mice in which the α1GABAA receptor had been rendered diazepam-insensitive by a point mutation [α1(H101R)] failed to be sedated by diazepam (Rudolph et al. 1999; McKernan et al. 2000). Ligands with preferential affinity for α1 receptors such as zolpidem or zaleplon are used as hypnotics. Similarly, the changes in the EEG pattern induced by zolpidem in wild-type mice were almost exclusively mediated via α1GABAA receptors (Kopp et al. 2004a). However, the changes in sleep architecture (suppression of rapid eye movement (REM) sleep) and EEG-frequency profiles (reduction of slow-wave sleep, increase in fast β-frequencies) induced by classical benzodiazepines are largely because of effects mediated by receptors other than α1 (Tobler et al. 2001). The most pronounced effect of diazepam on the sleep EEG in wild-type mice is derived from the enhancement of α2GABAA receptors. When the α2GABAA receptor was rendered diazepam-insensitive by a point mutation [α2(H101R)], the diazepam-induced suppression of δ-waves, the increase in fast β-waves in non-REM sleep (>16 Hz) and the diazepam-induced increase of θ-waves in REM sleep were strongly attenuated (Kopp et al. 2004b). Thus, the hypnotic EEG fingerprint of diazepam can be dissociated from its sedative action. Future hypnotics might target changes in the EEG pattern, which are characteristic of physiological sleep and thereby aim at improving sleep quality. For instance, the GABA-mimetic gaboxadol (4,5, 6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-0 L hydrochloride; synonym THIP), which interacts preferentially with α4β3δ GABAA receptors in vitro (Brown et al. 2002; Storustovu and Ebert 2003) was found to enhance slow-wave sleep in vivo (Lancel and Steiger 1999; Huckle 2004).

Receptor for anxiolysis

As α1GABAA receptors were found to mediate sedation but not anxiolysis (Rudolph et al. 1999; McKernan et al. 2000), the anxiolytic activity of benzodiazepines was expected to reside in one or several of the remaining benzodiazepine-sensitive GABAA receptors (α2, α3, α5). The differentiation of GABAA receptors by knock-in point mutations showed that it was the α2- but not the α3- or α5GABAA receptor which mediated the anxiolytic activity of diazepam (Löw et al. 2000; Crestani et al. 2002). In α2(H101R) mice, but not α3(H126R) or α5(H105R) mice, diazepam failed to induce anxiolytic activity (light-dark paradigm, elevated plus maze). With the α2GABAA receptor, a highly selective target for the anxiolytic activity of benzodiazepine tranquillizers had been identified. In keeping with this notion, the benzodiazepine site ligand L-838 417, which showed efficacy at α2, α3 and α5 but not α1GABAA receptors, proved to be anxiolytic in wild-type rats (Table 2) (McKernan et al. 2000). Similarly, partial agonists of 3-heteroaryl-2-pyridones acting at the benzodiazepine site with efficacy at α2, α3 and α5 receptors, but not at α1 receptors, were found to show anxiolytic activity in rodents (Table 2) (Collins et al. 2002). It remained to be clarified to what extent the α3GABAA receptor component contributed to the anxiolytic activity of these ligands. In mice which lacked α3GABAA receptors, the anxiolytic activity of diazepam was undiminished (Yee et al. 2005). However, an α3-selective inverse agonist was anxiogenic and proconvulsant in rodents (Table 2) (Collins et al. 2002). In addition, TP003 with selective efficacy at α3GABAA receptor was anxiolytic although only at high receptor occupancy (Dias et al. 2005). Classical benzodiazepines exert anxiolysis at low receptor occupancy, suggesting that the α2GABAA receptors and not the α3GABAA receptors are the major mediators of this activity. The contribution of α3GABAA receptors is unlikely to be of major relevance. Thus, the strategy to develop novel day-time anxiolytics, which are free of sedation, focuses on α2GABAA receptors although α3 receptors are not excluded (Möhler et al. 2002, 2005; Whiting 2003b) such ligands are expected to display low or no dependence liability (Ator, 2005).

Table 2.   GABAA receptor subtype ligands*
DrugMain activityInteraction with recombinant GABAA receptors1,2Reference
  1. *This table is a modified version from Rudolph and Möhler (2006).

  2. 1 Classical partial agonists which do not differentiate between GABAA receptor subtypes such as Bretazenil (Haefely et al. 1990) or Pagoclone (Atack et al. 2006b) are not considered in this review.

  3. 2 Data should be treated with caution as properties of recombinant receptors that are expressed in foreign host cells might not give an accurate reflection of their neuronal counterparts.

  4. 3 GABA is a weak partial agonist on δ-containing receptors, which largely explains the strong modulatory response of ligands acting on δ-containing receptors (Bianchi and MacDonald, 2003). THDOC, 5α-pregnane3α,21-diol-20-one.

A. Benzodiazepine site ligands
 ZolpidemHypnoticPreferential affinity for α1Dämgen and Lüddens, 1999
 ZaleploneHypnoticPreferential affinity for α1Dämgen and Lüddens, 1999
 IndiplonHypnoticPreferential affinity for α1Foster et al. 2004
 L-838 417AnxiolyticComparable affinity at α1, α2, α3, α5 subtype Partial agonist at α2, α3, α5 (not α1) subtypeMcKernan et al. 2000
 OcinaplonAnxiolyticComparable affinity at α1, α2, α3, α5 subtype. Partial agonist at α2, α3, α5 subtype, nearly full agonist at α1Lippa et al. 2005
 SL 651 498AnxiolyticAgonist at α2, α3, partial agonist at α1 and α5 subtypeGriebel et al. 2003
 TPA 023AnxiolyticPartial agonist at α2, α3 subtypes, antagonist at α1, α5 subtypesAtack et al. 2006a
 TPA 003AnxiolyticPartial agonist at α3 subtypeDias et al. 2005
 ELB 139AnxiolyticSelective receptor profile uncertainLangen et al. 2005
 L-655 708Memory enhancerPartial inverse agonist with preference for α5 subtypeSternfeld et al. 2004; Chambers et al. 2004; Navarro et al. 2002, 2004; Dawson et al. 2006
 A3 IAAnxiogenicWeak inverse agonist at α3Atack et al. 2005
B. Modulatory site other than benzodiazepine site
 EthanolAnxiolytic, SedativeHigh sensitivity (≥ 3mM) at α4 (α6) β3δ3; Medium sensitivity (≥ 30mM) at α4 (α6) β2δ3; Low sensitivity (≥ 100mM) at α4 (α6) β3γ2Wallner et al. 2006
 Neurosteroids (e.g. 3α,5α THDOC)Anxiolytic, Sedative AnaestheticHigh sensitivity at δ-containing subtypes 3and at α1, α3 receptors in combination with β1Belelli and Lambert 2005
 Intravenous anaesthetics (Etomidate Propofol)Sedative, AnaestheticAct on receptor subtypes containing β3 i.e. mainly α2 and α3 subtypesRudolph and Antkowiak 2004
C. GABA site
 GaboxadolHypnoticPartial agonist at α1, α3 subtypes, full agonist at α5 and superagonist at α4β3δ receptors2Stornstovu and Ebert 2003

α2GABAA receptors by their preponderant localization on the axon-initial segment of principal cells in cerebral cortex and hippocampus can control the output of these cells. In addition, α2 receptors are the only GABAA receptors found in the central nucleus of the amygdala, a key area for the control of emotions (Marowsky et al. 2004). Thus, by their strategic distribution in brain areas involved in anxiety responses, α2GABAA receptors are key substrates for anxiolytic drug action.

Receptor for associative learning and memory

Hippocampal pyramidal cells express various structurally diverse GABAA receptors in a domain-specific manner (Fig. 3). While α1- and α2GABAA receptors are largely synaptic, α5GABAA receptors are located extrasynaptically at the base of the spines and on the adjacent shaft of the pyramidal cell dendrite. The α5GABAA receptors are therefore in a privileged position to modulate the excitatory input arising at the spines via NMDA receptors. The introduction of a point mutation (H105R) in the α5 subunit is associated with a specific reduction of the hippocampal α5 subunit-containing GABAA receptors, while the pattern of distribution is undisturbed (Crestani et al. 2002). Mice with a partial deficit of α5GABAA receptors in hippocampus showed an improved performance in trace fear conditioning, a hippocampus-dependent memory task (Crestani et al. 2002). In addition, these mutants displayed a resistance to extinction of conditional fear over several days (Yee et al. 2004). Similarly, in a mouse line in which α5GABAA receptors were deleted in the entire brain (Collinson et al. 2002; Whiting 2003b), an improved performance in the water maze model of spatial learning was observed. Furthermore, a partial inverse agonist acting at α5GABAA receptors enhanced the performance of wild-type rats in the water maze test (Chambers et al. 2004) (Table 2). Thus, neuronal inhibition in the hippocampus mediated via α5 GABAA receptors is a critical element in the regulation of the acquisition and expression of associative memory (Fritschy et al. 2004).

It is striking that the behavioral consequences of an impairment of α5GABAA receptors are opposite to those of an NMDA receptor deficit as shown in spatial and temporal associative memory tasks. Infusion of AP5 into the brain caused a deficit in spatial learning performance (Morris et al. 1986). While mice with a deficit in hippocampal NMDA receptors show a deficit in the formation of spatial and temporal memory (McHugh et al. 1996; Tsien et al. 1996), the mice with a partial deficit of α5GABAA receptors in hippocampus display an improvement in spatial and temporal memory performance. Thus, it appears that these two receptor systems play a complementary role in controlling signal transduction at the hippocampal principal cells (Fritschy et al. 2004). While the initial results with α5-selective partial inverse agonist, described above, support a role in memory function, it has to be verified that such ligands do not interfere with other hippocampal functions such as sensorimotor gating (see below).

Receptor for sensorimotor processing

A deficit in GABAergic inhibitory control is one of the major hypotheses underlying the symptomatology of schizophrenia (Lewis et al. 2005). A potential contribution of GABAA receptor subtypes was therefore investigated with regard to the overactivity of the dopaminergic system, considered to be a major factor in schizophrenia. The dopaminergic system is under GABAergic inhibitory control mainly via α3-containing GABAA receptors (Fritschy and Möhler 1995; Pirker et al. 2000). Their functional role was explored in mice lacking the α3 subunit gene. α3-Knockout mice displayed no adaptive changes in the expression of α1, α2 and α5 subunits and anxiety-related behavior was normal. However, the mice displayed a marked deficit in pre-pulse inhibition of the acoustic startle reflex, pointing to a deficit in sensorimotor information processing (Yee et al. 2005). This deficit in pre-pulse inhibition was normalized by administration of the anti-psychotic D2 receptor antagonist haloperidol, suggesting that the phenotype is caused by hyperdopaminergia (Yee et al. 2005). Attenuation of pre-pulse inhibition is a frequent phenotype of psychiatric conditions including schizophrenia. These results suggest that α3-selective agonists may constitute an effective treatment for sensorimotor-gating deficits in various psychiatric conditions. This view is supported by the observation that the partial benzodiazepine site agonist bretazenil in earlier open clinical trials displayed an anti-psychotic activity similar to neuroleptic drugs (Delini-Stula and Berdah-Tordjman 1996). It is conceivable that the α3-selective agonists would lack the sedative or extrapyramidal side effects of classical neuroleptics and would thus be valuable therapeutic agents.

The hippocampus is believed to play an important role in the modulation of pre-pulse inhibition. In α5(H105R) point-mutated mice, the expression of the α5 subunit-containing GABAA receptors in the hippocampus is reduced (see above; Crestani et al. 2002). In these animals, pre-pulse inhibition was attenuated concomitant with an increase in spontaneous locomotor activity (Hauser et al. 2005). Thus, the α5 subunit containing GABAA receptors which are located extrasynaptically and are thought to mediate tonic inhibition (Caraiscos et al. 2004; Scimemi et al. 2005; Glykys and Mody 2006;Prenosil et al. 2006) (Fig. 3) are important regulators of the expression of pre-pulse inhibition and locomotor exploration. Post mortem analyses of schizophrenia brains have consistently revealed structural abnormalities of developmental origin in the hippocampus (Lewis et al. 2005). Such abnormalities may include disturbances of α5GABAA receptor function, given that schizophrenia patients are known to exhibit a deficit in pre-pulse inhibition. Thus, agonists acting on both α3 and α5 GABAA receptors may therefore be beneficial in overcoming this endophenotypic disease manifestation.

Receptor for consciousness

In the quest for neuronal correlates of consciousness (Koch 2004), various avenues are being followed, including the quest for the mechanism of action of anesthetic drugs by which consciousness is safely, painlessly and reversibly switched off and on again for surgical interventions. Various molecular targets have been invoked in mediating the clinical effects of general anesthetics (Franks and Lieb 2000; Campagna et al. 2003; Rudolph and Antkowiak 2004). Recent work focused on the role of GABAA receptors based on the analysis of point-mutated knock-in mice which carried point mutations in the β3 and β2 subunits of the GABAA receptor. These mutations rendered the GABAA receptors containing the respective subunits insensitive to modulation by the i.v. anesthetics propofol and etomidate and certain volatile anesthetics e.g. enflurane. It was found that β3-containing GABAA receptors mediate in full the immobilizing action of etomidate and propofol (Table 2) (Jurd et al. 2003), which correspond to the stage of surgical tolerance. Thus, β3GABAA receptors are a major control element for anesthesia. These receptors also mediate the immobilizing action of enflurane, isoflurane and halothane at least in part (Jurd et al. 2003; Lambert et al. 2005; Liao et al. 2005). In addition, they also mediate part of the hypnotic action of etomidate and propofol (Jurd et al. 2003), but apparently not that of the volatile anesthetics (Jurd et al. 2003; Lambert et al. 2005). In contrast, the hypnotic action of etomidate was found to be mediated by β2-containing GABAA receptors (Reynolds et al. 2003). Further studies revealed that the respiratory depressant action of etomidate and propofol is also mediated by β3-containing GABAA receptors, while the heart rate depressant action and to a large part the hypothermic action of etomidate and propofol are mediated by other targets (Cirone et al. 2004; Zeller et al. 2005). Thus, a β3-selective agent would be predicted to be immobilizing and respiratory depressant, but largely lack the heart rate depressant and hypothermic actions of etomidate and propofol. The analysis of α subunits involved in mediating the actions of general anesthetics is expected to result in further insights into the contribution of GABAA receptors to anesthesia. Mutations in α subunits have been identified in recombinant studies which render αxβxγ2 GABAA receptors insensitive to specific volatile anesthetics but not to etomidate or propofol (Mihic et al. 1997; Krasowski et al. 1998). It is expected that studies using knock-in mice carrying these mutations will yield further information on the contribution of individual GABAA receptors subtypes to anesthesia and thereby point the way to the circuits controlling consciousness.

Recombinant GABAA receptors containing the ε subunit instead of the γ2 subunit were found to be insensitive to general anesthetics (Davies et al. 1997). When the ε subunit was expressed at low levels, the resulting receptors were sensitive to general anesthetics (Thompson et al. 2002) although α/β receptors might be a confounding factor. In slices from rat brain stem, adenoviral expression of the ε subunit in cardiac parasympathetic pre-ganglionic neurons rendered GABAA receptors insensitive to pentobarbital (Irnaten et al. 2002). The functional role of the ε subunit requires further clarification.

Post-natal developmental plasticity

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

Apart from its trophic role in embryonal development (Represa and Ben-Ari 2005), GABA is a major determinant for post-natal developmental plasticity which has been investigated in different somato sensory systems. For instance, in the rodent somatosensory system, axons from each whisker form a somatotopic map in cortex, known as barrel map. During a critical period of neonatal development, this barrel map is fine-tuned in response to sensory experience based on a variety of synaptic mechanisms involving not only excitatory but also inhibitory circuits (Foeller and Feldmann 2004). The role of inhibitory circuits in synaptic reorganization is similarly apparent in the auditory system. Recent work has revealed a dramatic remodeling of inhibitory synapses shortly after the onset of hearing (aural dominance bands). The restructuring relies on both spontaneous and sensory-evoked neural activity (Kandler 2004; Linkenhoker et al. 2005). In the post-natal plasticity of the visual system, the role of GABAergic inhibition has recently been investigated in detail as outlined below.

In the visual system, postnatal developmental plasticity is most apparent in the formation of ocular dominance columns in layer IV of the primary visual cortex. Cortical territories receiving neuronal input from one eye alternate with territories from the other eye. Initially, at birth, the thalamic inputs from both eyes to the visual cortex are totally overlapping (Ferster 2004). It is only in the subsequent phase of remodeling that the separation of the visual inputs into ocular dominance columns arises. This process is sensitive to light as shown by the classical work on the influence of monocular deprivation on ocular dominance plasticity (Wiesel and Hubel 1963). After closure of one eye during a critical period of early post-natal life, the input from the open eye ends up with larger cortical territory than the input from the deprived eye. Critical period plasticity is best viewed as a continuum of local circuit computations, which result in a structural rewiring of thalamic afferents (Hensch 2005).

The mechanism of visual cortical plasticity was analyzed in detail with regard to the contribution of intracortical GABAergic transmission. GABAergic transmission was modulated locally by infusion of the benzodiazepine agonist diazepam or the inverse agonist methyl-6,7-dimethoxyl-4ethyl-beta-carboline-3-carboxylate (DMCM). Following chronic infusion of diazepam into striate cortex (starting at P14-P17), the spacing of ocular columns was widened while infusion of DMCM reduced the spacing (Hensch and Stryker 2004). The visual responsiveness remained undisturbed under these conditions (Hensch and Stryker 2004). Thus, intracortical GABA interneurons shape the geometry of the incoming thalamic arbors. In addition, the degree of GABAergic inhibition was found to be a key determinant for the onset of critical period plasticity. The enhancement of GABA transmission by diazepam was known to induce a premature onset of the critical period (Fagiolini and Hensch 2000). It was now found that only circuits containing α1GABAA receptors drive cortical plasticity, whereas α2-enriched connections separately regulate neuronal firing (Fagiolini et al. 2004). These results were based on the use of knock-in mice in which the respective individual α-subunit had been rendered diazepam-insensitive by a point mutation (Rudolph et al. 1999; Löw et al. 2000). These recent findings present a cellular and molecular basis for critical period plasticity triggered by inhibition in the visual cortex (Fagiolini et al. 2004; Ferster 2004).

For ocular stripes to form post-natally, activity in nearby inputs from the same eye is considered to co-operate with each other as cluster of cortical cells in their bid to take over cortical territory. Activity in more distant cells must be anti-correlated by means of lateral GABAergic inhibitory connections. Inputs from the same eye are therefore suppressed in their bid to take over the adjacent territories. In this way, the pattern of ocular dominance columns arises during the segregation of eye-specific inputs to the visual cortex in a self-organizing process. The cortex itself, through a specific GABAergic interneuron, plays a central role in organizing this pattern (Ferster 2004). The special function of neocortical α1GABAA receptors suggests constraints on drugs designated for use in human infants (Fagiolini et al. 2004).

Acknowledgement

  1. Top of page
  2. Abstract
  3. Why GABA?
  4. Multiplicity of distinct GABAA receptors
  5. Pharmacology of GABAA receptor subtypes
  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References

I would like to express my gratitude to my colleagues for their contributions to the investigation of the GABAA receptor system, in particular Dietmar Benke, Florence Crestani, Jean-Marc Fritschy, Takao Hensch, Bernhard Lüscher and Uwe Rudolph.

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  6. Post-natal developmental plasticity
  7. Acknowledgement
  8. References
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