Monday, 12 November 2012

GABA receptors

Alberts p 684
Chemical synapses can be excitatory or inhibitory.  
Transmitter-gated ion channels differ from one another. They havea highly selective binding site for NT released from presynaptic nerve terminal As channels they are selective in type of ions they let pass across plasma membrane. This determines nature of postsynaptic response.

Excitatory NTs open cation channels, causing Na+ influx  Depolarises postsynaptic membrane towards threshold potential for firing AP.

Inhibitory NTs open Cl- or K+ channels. Suppresses firing by making it harder for excitatroy influences to depolarise synaptic membrane.

Acetylcholine can excite or inhibit depending on type of receptors it binds to. Ach, gulutamate and serotonin as usually excitatory. GABA and glycine are inhibitory. Glutamate mediates most of excitatory signalling in vertebrate brain.

Cl- concentration is much higher outside cell than inside. Membrane potential opposes its influx. For many neurons equilibrium potential for Cl- is close to resting potential or more negative.

Opening Cl- channels buffers membrane potential. As membrane starts to depolarise, more negatively charged Cl- ions enter cell and counteract depolarisation.

Opening Cl- channels makes it more difficult to depoloarise membrane and hence excite cell. K+ channel opening has similar effect.

GABA-A receptors and their drug targets, Olsen and Sieghart

GABA are the major inhibitory NT in the brain. They mediate inhibition via GABAA receptors. GABAAR mediate rapid phasic inhibitory synaptic transmission.

Heterogeneity of GABAAR
GABAAR are composed of 5 proteins subunits of diff subunit classes  There are 19 genes for GABAAR subunits. 16 subunits (α1-6, β1-3, γ1-3, δ, ε, π) which are combined as GABAA. 3 ρ subunits contribute to GABAC receptors. They are subtypes of GABAAR containing ρ subunits.

GABAAR assembly as heteropentamers causes complex heterogeneiety in structure. This determines pharmacological profile.

Identifying native GABAA receptor subtypes by their regional and cellular distribution
In site hybridisation and immunohistochemical studies indicate that α1, β1, β2, β3 and γ2 subunits arefound throughtout brain. Differences in distribution.  α2, 3, 4, 5, 6, γ1 and δ are more confined to certain areas. In some brain regions a complementary distribution of &aopha; 2, 4, β3, and δ versus α1, β2 and γ2 subunits were detected. δ is freq co-distributed with α4 in thalamus, striatum, outer layers of cortex and dentate molecular layer. In cerebellum it is co-distributed with α6 subunit.

 A criterion for association of subunit isoforms into oligomeric native receptors is colocalistion of subunits.  Majority of GABAA receptors in brain is composed of α, β and γ subunits. Receptors composed of α1, β2 and γ2 subunits are extensively co-localised in subsets of GABAergic interneurons in hippocampus and other brain regions. α1β2γ2 receptors are most abundant GABAAR in brain.
α1 and 3 are expressed in GABAergic neurons.

Identifying native GABAAR subtypes by their synaptic and extrasynaptic localisations

Studies indicate that individual subunits show distinct subcellular distribution. In Cb GCs α1,6 β2/3 and γ2 have been found to be concentrated in GABAergic Golgi synapses. Also present in extrasynaptic membrane at lower concentration

δ subunits could not be detected in synaptic junctions though they were abundant in extrasynptic dendritic and semantic membranes.  Receptors cotaiing δ also contain α6 and β subunits.  Receptors containing δ subunits show a smaller single channel conductance and much longer open time. Do not desensitise on prolonged presence of GABA.  These propoerties indicate that tonic inhibition in cells is mediated mainly by persistent activation of  α6βδ recpetors by GABA present in extracellular space of glomeruli.

Extrasynaptic receptors have been found in other brain regions. Experiments suggest that tonic conductance can be enhanced by benzodiapines. This suggests that tonic inhibition can be produced by γ subunit-containing repecotrs. Due to larger cell surface earea, charge carried by activation of tonically active GABAAR can be more than 3 times larger than that produced by phasic inhibition.

Identifying native GABAAR subtypes by their subunit ocmposition
Subunits are promiscuous.  α and β subunits may be able to combine with most of other subunits to form a variety of diff receptor subtypes.  Studies indicate that 2 diff α and two diff β subunits can be present in GABAAR.

.Most studies agree that γ cannot be coprecipitated with other γ suibnits.  δ are not present with γ subunits in same receptors. Unit stoichimetry of 2α, 2β and 1γ or 1 δ subunits is deduced for native receptors.

Structural basis of GABAAR receptor pharmacology
GABAAR are members of Cys-loop pentameric LGIC superfamily. They are pentamierc membrane-spanning proteins surroundings a central pore which forms ion channel through the membrane. All use similar sequences and functional domains to establish membrane topology, ion channel structure, agonist binding sites and binding sites for diverse allosteric ligands.

Each subunit consists of a long N-terminal extracellular hydrophilic region, followed by 4 TM(M) α-helices with a large intracellular loop between M3 and M4.  Ends with a relatively short extracellular C-terminal domain. M2 forms lining of ion channel.

In extracellular domain there are 5 pockets at 5 subunit interfaces. 2 pockets at β/α interfaces form 2 GABA binding sites.  Pocket at α/γ interface forms benzodiazepine binding site. GABA pocket is formed by loops A, B, and C of principal side and loops D, E, F of complementary side.  Residues homologous to those in agonist bindings lopps at β/α interface are homologous in all members of superfamily.

Homology modelling of extracellular and TM domain based on nAChR indicates GABAAR  contains additional cavities in TM domain.  One set of putative pockets is an extension of EC pockets into lipid bilayer of TM domain.  Another type of cavity is found inside each of the subunits surrounded by the 4 helices that make up TM domain.  These cavities are probably needed for conformational changes of the receptors. May also serve as drug-binding sites. Bindings drugs into sites could stabilise or induce conformational changes on receptor and thus enhance or reduce GABA-induced chloride flux.

Identifying native GABAR subtypes by their pharmacology
Benzodiazepine bindings site at α+/γ- interface indicates that benzodiazepine pharmacology of receptor subtypes is mainly determined by α and γ isoforms forming this site.

Classical benzodiazepines eg diazepam or flunitrazepam predominantly interact with receptors composed of  αβγ2, α2βγ2, α3βγ2, or α5βγ2.No activity on α4βγ2 or α6βγ2 receptors. Reduced activity on receptors containing γ1 or γ3 subunits.

Glutamate-gated chloride (Cys-loop) channel from C. Elegans.
GluCl was crystallised.

Allosteric activation and modulation
Invermectin activates CluClα and renders receptor susceptible to further Glu activation.  Ivermectin is a partial allosteric agent.

Invermectin binds subunit interfaces on periphery of transmembrane domains. Proximal to EC side of membrane bilayer. Ivermectin is wedged between M3 and M1 α helices. It inserts deeply into subunits interface and makes contacts with M2 (+) pore-lining α-helix and M2-M3 loop.

Neurotransmitter-binding site
Ion channel of GluCl is activated by Glu only after activation by invermectin, an allosteric agent. Glu binds the classical NT site in the EC domain. It is lodged between subunits and nearly inaccessible to solvent. Arginine 37 and Arg 56 with neighbouring cationic aa provide binding pocket with positive electrostatic potential.

GluCl NT-binding pocket is selective for small discarboxylate L-amino acids.

It is suggested that invermectin, a partial allosteric agent, stabilises an active conformation of the agonist site. Binding of glutamate to this activated site further stabilises open state of receptor, increasing Cl- conductance.

Pore conformation
GluCl was crystallised with picrotoxin an open channel blocker. The ssmaller diameter of CluClcryst ion channel is 4.6 angstrom, defined by a hdrophobic gridle of 2' Pro side chains proximal to cytoplasmic side of membrane. Cl-, I- and other permeant ions through 2' Pro contsribtion involves dehydration. GluCl is related to the Torpedo nAChR.

Ion selectivity
Electropositive vestibule, a slightly electronegative EC half of TM pore an an electropositive IC half. None of the pore-lining residues in GluClcrys has formal charge.
The -2' residue defines the pore constriction  Deletion of -2' Pro in glycine receptors shifts the following Gly residue into 2' position, increases pore diameter. It is proposed that 2' position lines the pore in both anion and cation channels. and that anion pockets in CluClcrys determines ion selectivity, increasing local concentration of anions at cytoplasmic mouth of pore.

Diazepam-bound GABAa receptor models identify new benzodiazepine binding-site ligands by Richter
Benzodiazepines exert anxiolytic, anticonvulsant, muscle-relaxant and sedative-hypnotic properties by allosterically enhancing action of GABA at GABAA receptors via benzodiazepine-binding site.

Rudolph and Mohler: Analysis of GABAAR function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics
Point mutations were introduced into mouse genome. Idea is point mutation will leave physiological function of receptor subunit and receptor complex intact, avoiding developmental compensatory mechanisms  Point mutation would spec prevent modulation of respective receptor by defined drugs.

α1 (H101R) knockin mice
In wt mice, diazepam decreases horizontal motor activity. This effect was absent in α1 (H101R) mice. Thus Wt mice α1-containing GABAAR mediate sedative action of diazepam.

The neurosteroid 3α-hydroxy-5β-pregnan-20-one decreased motor activity in wt and mutant mice to same extent  Shows that lack of drug-induced sedation is restricted to benzodiazepine site ligands.

Diazepam protects wt mice from pentylentetrazole-induced myoclonic jerks and tonic seizures. Mutant mice are only partially protected. Anticonvulsant activity of diazepam is mediated in part by α1- containing GABAAR. Anticonvulsant activity of sodium phenobarbital was indistinguishable in wt and mutant nice.

When mutant mice are tested in novel env, diazepam increases locomotor activity. This is likely mediated by α2, 3 and 5 containing GABAAR. In familiar env, diazepam decreases motor activity in wt bu not in α1 (H101R) mice.

In α1(H101R) mice diazepam retains its anxiolytic-like activity in light/dark choice test and elevated plus maze test, its myorelaxant activity in horizontal wire test and its ethanol-potentiating effect. This indicates that these activities are mediated by GABAAR containing α2, 3, and 5 subunits.

When α1(H101R) mice are treated with diazepam, it shows agonist activity at α2, 3 and 5 containing GABAAS.

Observed diazepam-induced changes are not mediated by α1-containing GABAAR.

α2(H10R) Knockin Mice
α2-containing GABAAR are expressed in limibic system in regions involved in emotional stumulus processing eg amygdala and hippocampus.

In ligh-dark test and elevated plus maze test, diazepam, increased time mice spent in lit comparment or open rams in wt mice. Not in α2 (H101R) mice. This indicates that α2-containing GABAAR mediate anxiolytic-like action of diazepam.

Normal sedative and anticonvulsant responses to diazepam but myorelaxant action was impaired.

Molecular and neuronal suibstrate for selective attenuation of anxiety by Low
Anxiolytic action of diazepam was absent in mice with α2(H101R) point mutation but present in mice with α3(H126R) point mutation. Anxiolytic effect of BZ drugs are mediated by α2 GABAAR largely expressed in limib syste, but not by α3 GABAAR in the reticular activating system.

Diazepam reponse was compared in α2(H101R) and α3(H126R) and wt mice.  Sedative, motor-impairing and anticonvulsant action of diazepam were not impoaired in α2(101R) and α3(H126R) relative to wt mice.

Anxiolytic like action was investigated in light dark choice test and elevated plus-maze test. In light dark choice test, α2 (101R) mice did not show behavioural disinhibition by DZ in wt mice.  DZ up to 2 mg/kg body weight did not increase time spent in lit area. No behavioural differences in dark.

α2(H101R) mice retained ability to display anxiolytic-like response to ligands acting at GABAAR sites other than BZ site. Sodium phenobarbital induced behavioural disinhibition in light/dark choice test similar to that seen in wt mice.

In plus maze test, for wt mice, DZ facilitated exploratory behaviour.  Increased time spent and number of entries in open arms. In α2(H101R) mice, DZ did not increase both parameters.

α3(H126R) and wt mice showed similar dose-dependent anxiolytic like responses to DZ in light/dark test and elevated plus-maze. Indicates that anxiolytic action of DZ in wt mice do not involve interaction with α3 GABAAR.

Anxiolytic-like action of DZ is selectively mediated by enhancing GABAergic transmission in a population of neurons expressing the α2 GABAAR which represents only 15% of all DZ sensitive GABAAR. α2GABAAR-expressing cells in cerebral cortex and hippocampus include pyramidal cells that show very high densities of α2 GAAR on axon initial segment. α2 GABAAR are highly spec targets for development for future selective anxiolytic drugs.

Beyond the classical benzodiazepines: novel therapeutic potential of GABAAR subtypes by Rudolph and Knoflach
BZ bind spec sites in CNS which are modulatory sites on GABAAR.  In α(H101R) mice sedative action and anterograde amnestic action of DZ wa absent. Anticonvulsant action was reduced.  Anxiolytic like action was present.  In α(H101R) mice the anxiolytic-like action of DZ was absent and myorelaxant action was reduced. Sedative action was present.  In α3(H126R) mice and α5(105R) miec the myorelaxant action of DZ was reduced. Sedative and anxiolytic-like actions were present.

Sedative, anterograde, amnestic and partyl anticonvulsant actions of DZ are mediated by α1-containing GABAAR. Anxiolytic-like and myorelaxant actions are mdiated by α2-containing GAAAR. Myorelazant action is mediated partly by α3- and -5 containing GABAAR.

Binding and functional selectivity
Ligands at BZ site of GABAAR are allosteric modulators. They modify efficacy and/or affinity of agonists and regulate activity. Modulation can be positive, negative or neutral. It is achieved by stabilising diff conformations of receptor.

Selectivity of a ligand for a spec GABAAR subtype can be obtained by affinity or efficacy. Affinity is by forming or not forming a receptor-ligand complex.  Efficacy is obtained by eliciting or not biological response after binding receptor  These define potency profile.

Subtype selectivity is also assessed in electrophysiological experiments with human embryonic kidney 293 cells or Xenopus laevis oocytes expressing GABAAR receptor subtypes.

Activation of neuronal GABAAR results in hyperpolarisation. GABA is main inhibitory NT on CNS.  GABAAR are allosterically modulated by benzodiazepines used for sedative, anxiolytic, anticonvulsant and muscle relaxant action.

BZs have sedative-hypnotic properties. Theyare undesirable side effects when BZ used for other purposes eg daytime anxiolysis. It is important to identify receptor subtypes that mediate sedative action of BZs.

Other compounds have been dev eloped that either bind to same site as BZ or bing an overlapping site. Eg. Zolpidem has a high affinity for α1-containing GABAAR, a 20fold lower affinity fo α2-containing GABAAR ang α3-containing GABAAR and no affinity for α5-containing GABAAr.  It is α1-selective. It is used to treat insomnia.  α1-containing GABAAR are important targets for sedative-hypnotic action of zolpidem.

In α1-(H101R) mice the motor sedative action of zolpidem was abolished. This shows that sedative action was mediated by α2-containing GABAAR.

In α1(H101R) mice DZ increases sleep continuity. But its motor sedative effect is absent. This indicates that motor sedation is medtiated by α1-containing GABAAR but enhancement of sleep continuity occurs independently of α1-containing GABAAR.

Reduction of sedative effects
α2-containing GABAAR mediate anxiolytic-like actions of DZ. α1- GABAAR mediates sedative action of DZ.  A ocmpound seelctive for α2-containing GABAAR but has not activity at α1-containing GABAAR may be a non-sedating anxiolytic.

L-838417 is a partial positive allosteric modulator at α2, 3 and 5-containing GABAAR and an antagonist at α1-containing GABAAR. Pharmacological profile is non-sedating anxiolytic in mice and primates. Unfavourable pharmakinetic properties.

TPA023 or MK-0777 is an α2/α3-selective positive allosteric modulator. Has anxiolytic but not sedative effects in rodents. Has 0 efficacy at α1, 11% efficacy at α2, 21% efficacy at α3 and 5% efficacy at α5.

Ocinaplon has anxillytic but not sefative effects in rodents and humans. It was not further developed due t heptaic toxicity issues.

MRK409 is a positive allosteric modulator with higher efficacy at α3-containing GABAAAR but no binding selectivity. Anxiolytic in rats and primates but produced sedation in humans at low levels of receptor occupancy.  Exps with rodents and primates may not predicy accurately whether a compound is sedative in humans.

GABA system in anxiety and depression and its therapeutic potential by Möhler
Novel GABA anxiolytics in humans
Anxiolytic activity includes α2 and α3 GABAAR. TP003 a ligand with selective efficacy at α3 GABAAR required 75% receptor occupancy at minimally effective dose. α2 receptors only mediate anxiolysis at low recept occupancy of 20%. TPA023 was effective. But cataracts at high doses in an animal species.

Eszopiclone as anxiolytic
Has high in vitro potency for α5 (EC50=25nM). Comparable potency for α2 and 3 (99 and 102nM). Low potency for α1 receptors (240nM).  Acts preferentailly via α2 and 3. α1 receptors contribute at higher doses. Showed anxiolyitc activity in a rodent model.  Appears to be effective.

Low potency GABAAR modulator. Efficacy at all BZ-sensitive GABAAR. Anxiolytic activity is mediated by α2 GABAAR.  Sedation by potential receptor occupancyat α1 does not appear to be pharmacologically relevant at anxiolytic doses. In a study it was anxiolytic without typical BZ side effects. Study terminated due to liver problems in one patient.

Translocator protein (TSPO) ligands
TSPO promotes transport of cholesterol through mitochondrial membranes. Rate limiting for synthesis on neurosterios which act on GABAAR. XBD173 acts as agonist at TSPO with nM affinity. Its anlytic activity is based on steroiogenic mech.  XBGD173 counteracted pharmacologically induced panic reactions in rodents. Chronic treatment did not induce sedation, tolerance or withdrawal effects. In human volunteers it suppresed panic anxiety.

Molecular and neuronal substrates for general anaesthetics by Rudolph and Antkowiak
Sedation and hypnosis (unconsciousness)
AT sedative concentrations propofol reduces neuronal activity in cortical networks.  At higher hypnotic concentrations subcortical structures inc thalamus, midbrain, reticular formation and possibly hypothalamus, affected. During propofol-induced hypnosis, glocal cerebral blood flow and glucose metabolism seem to be decreased. Some brain areas show higher degree of depression than others.  With loss of consciousness, lsow-wave actibity in delta band becomes more prominent. Fromntal beta power decreases. Indiciates a shift from cortical to subcortical generator regions.  Decrease in cortical glucose metabolism during transition from sedated to unconscioues state, reduced relative beta, alpha and theta power. Delta pwoer increased.  It is reasoned that decreased excitation dhifts firing mode of thalamic delay neurons from tonic to burst pattern, producing delta activity.

Theta power is rhythmic neural activity with freq of 4-12 Hz.  Delat power is rhythmic neural acitivity with freq of 1-4 Hz charactersitic of stage III and IV non-rapid eye movement sleep (slow-wave sleep).

Anaesthetic action in GABAAR receptor knockout mice
In β3 knockout mice, duration of loss of righting reflex in response to midazolam and etomidate was reduced compared to wt.

In recombinant α1β2γ2 amd α2β3γ2 receptors, replacing Aspargine 265 with Met in β2 or β3 subunit caused decrease in modulatory actions of etodimate, propofol and enflurane and direct agonist actions of etomidate and propofol.
On binding of GABA (gamma-aminobutyric acid; yellow dots) to the pentameric GABAA receptor complexes, chloride flows into the postsynaptic neuron, leading to hyperpolarization. Synaptic GABAA receptors (pink) have a low potency and a high efficacy, whereas extrasynaptic GABAA receptors (blue) have a high potency and a low efficacy. GABAA receptors that contain the delta- and the beta3 subunit, which are located extrasynaptically, have an increased sensitivity to ethanol in vitro, and it has been suggested that they might be important targets for general anaesthetics70b | General anaesthetics prolong channel opening and increase postsynaptic inhibition. c | A pentameric GABAA receptor complex in the lipid bilayer membrane.
The wild-type beta2 and beta3 subunits have an asparagine (Asn) residue at position 265 in the second transmembrane region. GABAA (gamma-aminobutyric acid, type A) receptors that contain these subunits are sensitive to propofol and etomidate. In beta2(N265S) mice, the Asn is changed to serine (Ser), the residue that appears at this site in the beta1 subunit67. Receptors that contain this mutation are largely insensitive to etomidate, but are sensitive to propofol. In beta3(N265M) mice, the Asn is replaced by a methionine (Met), which occurs in the corresponding position of the Drosophila melanogaster RDL receptor66. These receptors are insensitive to etomidate and propofol.
β3(N265M) mice, the point mutation abolishes modulatory and direct effects of etomidate and profol in vitro and reduced modulatory actions of enflurane.

Duration of loss of righting reflex in response to etomidagte and propofol was reduced compared to wt mice. Hypnotic activity is mediated partly by GABAAR containing β3 subunit and in apart by other targets.  Loss of hindlimb-withdrawal reflex was almost absent in β3(N265M) mice.  Immobilising action of drugs depends on GABAAR that contain β3.

β2(N265S) mutation reduces sensitivity to etomidate but not profol.  In Cb purkinje cells, the potentiating effect of etomidate was severely reduced.  After intravenous injection of etomidate the duration of loss of righting reflex was smaller in mutant than wt mice.  Duration of loss of righting reflex indistrinuishable in response to propofol. Indicates that function of β2-containing GABAAR is well preserved in mutant mice. Low doses of etomidate decreases locomotor activity and etomidate-induced impairment of rotarod performance was absent in mutant mice. Shows that sedative action of low doses of etomidate is mediated by β2-containing GABAAR. Immobilising action of etomidate is intact in mutant mice. Thus GABAAR with β2 do not mediate this action.

Immobilising action is mediated by β3 whereas hypnotic action is mediated by β3 and 2. Sedative action is mediatd by β2.

Propofol exerts anaesthetic action through same target as etomidate.  β2- GABAAR mediate sedative action of etomidate and presumably propofol is consistent with finding that α1- GAABAAR mediate sedative action of diazepam. Consistent wtih hypothesis that cortical α1β2γ2 GABAAR are responsible for sedative action of CNS-depressant drug.

Variations on an inhibitory theme: phasic and tonic activation of GABAAR by Farrant and Nusser, Nature Reviews Neuro

Modes of GABAA receptor activation
Phasic receptor activation. 
GABAAR-mediated synaptic communication allows rapid and precise transmission or presynaptic activity into postsynaptic signal. When AP arrives at nerve terminal, Ca2+ influx triggers fusion of synaptic vesicles at presynaptic membrane. Vesicles release GABA molecules into synaptic cleft, generating a peak GABA concentration in millimolar range. Opposite the release site are receptors. Receptors experience increase in GABA concentration. For a proportion of receptors, GABA binding triggers opening of their ion channels. The GABA transient to which the postsynaptic receptors are exposed is short in duration. GABA diffuses rapidly from release sote.

Brickley and Mody 2012
Extrasynaptic GABAA receptors enable nruons to sense low ambient GABA concentrations in EC space. This generates tonic inhibition. Important in regulating states of consciousness  Extrasynaptic GABAAR are believed to be targets for anaesthetics, sleep-promoting rugs, neurosteriods and alcohol.

These GABAARs are excluded from synapses. A persistent tonic conductance was indicated to result from activation of extrasynaptic GABAAR populations from whole-cell patch-clamp recordings made from developing neurons when synapses are being formed.  GABAAR blockers reduced standing holding current. This indicates that a tonic GABAAR-mediated conductance must be present not associated with conventional IPSCs. Early developmental forms of GABA signalling may play a role in controlling neuronal differentiation.

Subunit identity of final assembly determines synaptic or extrasynaptic localisation of GABAARs in a neuron.

Extrasynaptic α6βδ subunit-containing GABAARS mediate tonic inhibition in vitro and in vivo. Conventional synaptic γ2-containing GABAARs are involved in direct synaptic transmission.  A tonic conductance mediated by α4βδ subunit-containing GABAARs found in dentate gyrus cells.  A tonic conductance present in Ivy/neurogliaform cells is probably generated by persistent activation of extrasynaptic α1βδ subunit-containing extrasynpatic GABAARs.

Persistently active δ-GABAARs openings make a major contribution to total charge that flows across membrane. This conductance can modulate cell and network behaviour.

Tonic conductance does not alwyas results in membrane hyperpolarisation. In Cb GCs the membrane shunt associated with tonic inhibition attenuates excitatory drive with little impact on membrane potential. Shunting inhibition assoc with tonic conductance could result in small but persissten membrane depolarisation.

Tonic conductance in adult neurons represents simultaneous opening of a very small fraction of available extrasynaptic GABAARs. This indicates receptor occupancy is low and or a large number of receptors are heavily desensitised.

Tonic inhibition can be generated by desensitised receptor population as long as receptor number is high. But this could limit ability of receptors to operate as spillover detectors.  Other less desensitised GABARs could suit role better. Slow-rising and slow-decaying IPSCs generated by GABA spillover is significant feature of Ivy/neurogliaform cells  and found in hippocampal neurons.

Other GABAAR types can also generate a tonic conductance in adult brain regions. Eg α5βγ2 subunit-containing GABAARs generate a tonic conductance that regulates excitabilit of pyramidal neurons and CA1 and CA3 regions of hippocampus.

Spec high-affinity GABAAR popularions are predominantly responsible for generating tonic conductance found in many brain regions in normal physiological conditions.

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