Abstract

GABA_A receptors (GABARs), the main inhibitory neurotransmitter receptors in the mammalian brain, exist in a multitude of subtypes, including forms that predominantly mediate fast inhibitory synaptic transmission and other highly GABA-sensitive extrasynaptic forms that mediate tonic inhibition. GABARs are heteropentameric proteins formed by three different, yet homologous, subunits. Synaptic and extrasynaptic GABARs are targets of some medications used clinically in the treatment of seizures and epilepsy, including the barbiturates phenobarbital, primidone, and pentobarbital; propofol, and the neuroactive steroid ganaxolone. Synaptic GABARs are the targets of benzodiazepines, including diazepam, lorazepam, midazolam, and clobazam. Other epilepsy medications may also interact with GABARs in addition to affecting other antiseizure targets. This chapter gives a brief history of the GABAR involvement in the epilepsies and then describes developments since the publication of the last volume in this series in 2012. Greater understanding of the roles of GABAR isoforms has suggested strategies to target subpopulations of GABAR to more effectively treat various types of epilepsy and its comorbidities. Subtype specific GABAR positive modulators that selectively act on α2, α3, and α5 GABAR isoforms, and may have enhanced efficacy and reduced tolerance liability, are under investigation.

GABA_A Receptors in Epilepsy and as Therapeutic Targets

GABA_A receptors (GABARs), which are members of the pentameric ligand-gated ion channel (pLGIC) gene superfamily, are the main receptors mediating rapid inhibitory neurotransmission in the central nervous system and as such regulate excitability broadly in the brain. Understanding the central role of inhibitory neurotransmission has been a major focus of epilepsy research since William Gowers in the 1880s posited that the overactivity of seizures might be initiated by local loss of inhibition (Eadie, 2011). Since that time many studies have observed abnormalities in the function of GABA-dependent inhibitory mechanisms in genetic and acquired animal models of epilepsy (Treiman et al., 2001; Fritschy, 2008). Pharmacological observations have played a key role in the conviction that GABA-mediated neurotransmission regulates seizures. Drugs such as pentylenetetrazol, bicuculline, and picrotoxinin that inhibit GABAR induce seizures, whereas drugs that enhance GABAR function inhibit seizures. GABAR-positive allosteric modulators have important roles in the acute treatment of seizures and the chronic treatment of epilepsy. Among clinically used agents of this type are benzodiazepines, propofol, barbiturates, stiripentol, and the neuroactive steroid ganaxolone. The 1,4-benzodiazepines diazepam, lorazepam, and midazolam are used to terminate seizure emergencies, including acute repetitive seizures (seizure clusters) and status epilepticus. Refractory status epilepticus is often treated by general anesthesia with propofol or the barbiturate pentobarbital. The barbiturates phenobarbital and primidone, in the past, and now more commonly the 1,5-benzodiazepine clobazam are among the drugs routinely used chronically to prevent the occurrence of seizures. Ganaxolone (see Reddy and Rogawski, 2012) is approved to treat the rare developmental and epileptic encephalopathy (DEE) CDKL5 deficiency disorder, but it and other neuroactive steroids with GABAR-positive modulatory activity have broad potential in the chronic treatment of epilepsy and in the acute treatment of ongoing seizures.

The physiology and pharmacology of GABAR were covered extensively in Jasper’s Basic Mechanisms of the Epilepsies, fourth edition (Cherubini, 2012; Walker and Kullmann, 2012; Bernard, 2012; Crunelli et al., 2012; Joshi and Kapur, 2012; Mody, 2012). Additionally, the anatomy of brain GABAR relevant to epilepsy was described in detail (Houser et al., 2012; Sloviter et al., 2012: Ribak et al., 2012). The biochemistry of GABAR to 2011 has also been well reviewed (Whiting, 2003; Rudolph and Möhler, 2004; Brooks-Kayal and Russek, 2012; Olsen and Spigelman, 2012). In the past decade, major advances have been made in understanding the role of genetic variants in GABARs in the pathogenesis of epilepsy (Oyrer et al., 2018; Maljevic et al., 2019). Initially, it was found that inherited variants in the γ2- and α1-subunit genes, GABRG2 and GABRA1, cause relatively mild forms of inherited monogenic epilepsies, specifically generalized epilepsy with febrile seizures plus (GEFS+), childhood absence epilepsy, febrile seizures, and juvenile myoclonic epilepsy (Wallace et al., 2001; Lachance-Touchette et al., 2011; Kang and Macdonald, 2016). In addition, in cases of childhood absence epilepsy, heterozygous missence mutations were found in the GABRB3 gene encoding β3-subunits (Tanaka et al., 2008). These mutations were associated with a hyperglycosylation of the β3-protein and reduced GABAR current. Furthermore, loss-of-function GABRB3 mutations have been associated with neurodevelopmental disorders with autism and seizures, including Angelman and Rett syndrome (Tanaka et al., 2012). More recently, de novo variants in several GABAR genes, including GABARA1 as well as GABRB2 and GABRB3, encoding the α1-, β2-, and β3-subunits, have been found to cause severe early-onset DEEs such as Ohtahara syndrome, West syndrome, and Dravet syndrome (Carvill et al., 2014; Johannesen et al., 2016; Hernandez et al., 2017; Hernandez et al., 2019; Møller et al., 2017). Additional subunit genes in which variants have been associated with such severe early-onset epilepsies are GABRA2 and GABRA5, encoding α2- and α5-subunits; GABRG2; and the X-linked gene GABRA3, encoding α3. Disease-causing mutations in these genes generally lead to loss of GABAR function, but this can occur to different extents and by a wide variety of mechanisms. Loss of GABAR function can occur by impaired surface expression, nonsense-mediated messenger RNA decay, endoplasmic reticulum-associated retention and protein degradation, dominant negative suppression, and gating defects (Kang and Macdonald, 2016). In cases where there is a trafficking deficit due to endoplasmic reticulum retention, it has been proposed that misfolded mutant subunit proteins may progressively accumulate and form aggregates inside neurons, which may impair neuronal function and lead to neurodegeneration. In addition, mutations in GABRD, encoding the δ-subunit, have been associated with atypical absences, generalized myoclonic seizures, and generalized tonic-clonic seizures (Shen et al., 2017; Ahring et al., 2022). Paradoxically, the mutations in GABRD causing seizures were gain-of-function, mainly causing enhanced channel open probability (Ahring et al., 2022). Gain-of-function variants in GABRB3 have also been associated with DEEs (Absalom et al., 2022). Patients with gain-of-function variants are more likely to be severely affected than those with loss-of-function variants. They have seizure onset at younger ages, are more likely to have focal seizures and to be at risk of severe intellectual disability, and they are less likely to achieve seizure freedom with medications. Moreover, it is now apparent that variants in all GABAR genes are enriched in common forms of epilepsy, including rolandic epilepsy and genetic generalized epilepsy. This highlights the pivotal role of GABA_A receptors in epilepsy. The present chapter reviews some new developments in the field of GABAR research that are of particular relevance to an understanding of seizures and epilepsy, and it provides an update on current attempts to develop drug treatments that target GABAR.

GABAR Structure

GABARs are heteromultimeric proteins composed of five subunits, where each subunit is a linear chain of about 450 amino acids. There are 19 human GABAR subunit genes. The protein subunits encoded by these genes are organized into groups based on sequence similarity. The 19 expressed protein subunits [gene designations] are α(1–6) [GABRA1, GABRA2, GABRA3, GABRA4, GABRA5, GABRA6], β(1–3) [GABRB1, GABRB2, GABRB3], γ(1–3) [GABRG1, GABRG2, GABRG3], δ [GABRD], ε [GABRE], θ [GABRQ], π [GABRP], and ρ(1–3) [GABRR1, GABRR2, GABRR3]. Despite the potential for enormous receptor heterogeneity, diversity is constrained by assembly rules (Mortensen et al., 2012). Indeed, the majority of synaptic GABAR contain two α-subunits, two β-subunits, and a γ-subunit (Farrar et al., 1999). These GABARs can diffuse laterally in the neuronal membrane so that they are also found extrasynaptically. GABARs that are exclusively extrasynaptic contain a δ-subunit and often a specific α-subunit, such as α4 in thalamic relay cells or dentate granule cells, or α6 in cerebellar granule cells. An additional extrasynaptic GABAR type is α5βγ (Glykys et al., 2008). The N-terminal hydrophilic segment of each subunit is extracellular, and the linear protein chain has four transmembrane α- helical segments (designated M1–M4), which end with an extracellular C-terminal segment. Between the M3 and M4 segments, there is a large intracellular loop (Olsen and Sieghart, 2008). All subtypes of GABAR receptor are chloride ion channels that open after GABA binding.

GABAR Subtypes

Inhibitory GABARs are found throughout the brain, at synapses and also extrasynaptically, on excitatory principal neurons as well as on inhibitory interneurons (Ferando and Mody, 2014; Pelkey et al., 2017). GABARs localized to synapses mediate rapid inhibitory events on a time scale of milliseconds activated by large (~1 mM) GABA transients in the synaptic cleft. These phasic events are referred to as inhibitory postsynaptic potentials. In contrast, tonic inhibition is mediated by extrasynaptic GABARs that are persistently activated by low levels (100–1,000 nM) of GABA in the extracellular space. Interneurons that utilize GABA as their neurotransmitter and, in the cortex constitute 20%–30% of neurons (Markram et al., 2004), synapse onto excitatory principal neurons and also onto diverse classes of interneurons. At synapses GABARs mediate feed-forward inhibition, feedback inhibition, and disinhibition (presynaptic inhibition of GABA release). GABA released from an interneuron may also feed back onto the same neuron in an autocrine fashion. The various forms of synaptic and nonsynaptic GABA-mediated neurotransmission ultimately serve in the generation of the temporally precise activity of neuronal circuits and in the synchronized oscillatory behavior of neuronal populations (Engin et al., 2018).

The type and speed of inhibition generated by GABAR subtypes composed of different subunit compositions vary as a result of differences in channel-gating properties and localization within the neuron. The trafficking to and localization of GABARs to different neuronal zones also depend on receptor subunit composition. In diverse brain regions, α2- and α3-subunit-containing GABARs are highly concentrated at synapses, where they mediate phasic inhibition. In contrast, α4- and α5-subunits are found primarily at perisynaptic and extrasynaptic sites where they mediate tonic inhibition. As an example, somatic inhibitory synapses onto rat hippocampal CA1 pyramidal neurons contain α1-, α2-, and β3-subunits (Kasugai et al., 2010). By virtue of their location proximal to dendrites where the bulk of excitatory inputs converge onto the pyramidal neuron, these GABARs are well positioned to counter dendritic depolarization and suppress action potential generation in the target neuron. It is noteworthy that synaptic α1 and α2 GABAR subtypes are differentially located within hippocampal pyramidal neurons: those containing α1-subunits are preferentially expressed in dendrites, whereas those containing α2-subunits tend to be enriched at axoaxonic synapses at the axon initial segment, the site of action potential initiation (Nusser et al., 1996; Nyíri et al., 2001). There are also α1, α2, and β3-subunits located extrasynaptically, but the physiological role of this subpopulation is poorly understood inasmuch as GABA-mediated tonic inhibition is a function of GABARs containing α4- and α5- and/or δ-subunits (Belelli et al., 2009). Since synaptic γ2-containing receptors require high GABA concentrations to be activated, any such receptors that may be in the extrasynaptic compartment are essentially silent with repect to the low extrasynaptic GABA concentrations.

Targeting GABAR Subtypes for Epilepsy Therapy

An understanding of the behavioral roles of different GABAR subtypes provides a basis on which to conceive of improved seizure and epilepsy treatments that target specific receptor subtypes (Table 48–1). Nonselective GABAR-positive modulators have broad-spectrum antiseizure activity but, with the exception of clobazam, are not widely used in the chronic treatment of epilepsy because they induce dose-limiting side effects, including sedation and ataxia, and are subject to tolerance. Studies in mice with α-subunit mutations (H101R) that confer benzodiazepine-insensitivity along with subtype-selective modulator drugs, including L-838,417, a partial positive modulator of α2-, α3-, and α5-containing GABARs, have allowed a definition of the roles played by specific subunit compositions in the antiseizure and other pharmacological actions of drugs acting on GABARs. Early studies led to the conclusion that α1 is largely responsible for antiseizure activity (Rudolph et al., 1999; McKernan et al., 2000; Crestani et al., 2002). More recent studies indicate that α1-subunits have a contributory role, but the newer evidence indicates that α2 outweighs α1 in importance and that α5 may play a role (Löw et al., 2000; Fradley et al., 2007). In contrast, sedative actions are mediated primarily by receptors containing α1-subunits; anxiolytic actions primarily by receptors containing α2 subunits; and myorelaxant actions by receptors with α2-, α3-, and α5-subunits. This has led to interest in positive modulators that may bind but do not positively modulate α1, and selectively potentiate α2 and/or α5 (Solomon et al., 2019). The earliest example of this was TPA023, which binds with high affinity to α1 but is inactive as a positive modulator of receptors with this subunit and has modest efficacy at α3 > α2 > α5 (Atack et al., 2006). TPA023 is effective as an antiseizure agent, conferring about 50% seizure protection with 50% occupancy of brain benzodiazepine receptors. Like TPA023, L-838,417, imidazenil, and TPA023B are α1 antagonists and α2,α3, and α5 partial positive modulators with antiseizure activity (McKernan et al., 2000; Kadriu et al., 2009; Atack et al., 2011). It is hoped that such agents will retain the powerful antiseizure activity of nonselective GABAR modulators and avoid the side effects of sedation and ataxia. This strategy has so far not been successful in producing clinically useful anxiolytics. In clinical trials, all such compounds produced more sedation, dizziness, drowsiness, and motor incoordination than was predicted (Cerne et al., 2021).

Table 48–1

GABAR Subtypes as Targets in the Treatment of Seizures and Epilepsy.

Tolerance

Tolerance to the antiseizure effects of benzodiazepine-like GABAR modulators is perhaps the most important impediment to their widespread use in the chronic treatment of epilepsy. The physiological basis of benzodiazepine tolerance is not fully understood. Various effects of persistent exposure to a benzodiazepine have been implicated, including (1) uncoupling of the allosteric link between the GABA and benzodiazepine recognition sites such that binding to one site increases affinity at the other; (2) changes in GABAR subunit surface expression; and (3) post-translational modifications of the receptor (Gravielle et al., 2016). There is evidence that benzodiazepine-like modulators that lack α1 activity may have reduced tolerance liability (Cheng et al., 2018). In fact, imidazenil, which has low intrinsic activity at α1-subunit-containing GABAR, has been reported to be devoid of anticonvulsant tolerance following protracted administration (Auta et al., 1994, 2008; Zanotti et al., 1996). It has also been reported that the α2,α3-selective imidazodiazepines HZ166 and KRM-II-81 fail to exhibit anticonvulsant tolerance (Rivas et al., 2009; Cerne et al., 2021). Apart from the role of the α1-subunit, there is evidence that partial benzodiazepine modulators may also have reduced propensity for tolerance (Hernandez et al., 1989). TPA023, L-838,417, imidazenil, and TPA023B are no longer under development. Abecarnil, also no longer in development, is a full α1 agonist but partial α2 and α5 agonist, and may have reduced liability for tolerance (Natolino et al., 1996; Kasteleijn-Nolst Trenité et al., 2016). However, darigabat (PF-06372865, CVL-865) has similar pharmacological properties and is actively in development as an antiseizure medication (Janković et al., 2021). Darigabat has high affinity for GABAR containing an α1-, α2-, α3-, or α5-subunit and, as is the case for conventional benzodiazepine site ligands, has no affinity for GABAR containing α4- or α6-subunits. The rank order of affinity of darigabat at GABAR subunits is α1 > α3 ≈ α2 > α5. Despite the high binding affinity for α1 subunit GABARs, darigabat has low (~15%) efficacy for positive modulation of human α1 GABARs (Nickolls et al., 2018). At α2, darigabat is a partial positive modulator, maximally potentiating α2-containing GABAR only about 35% that of diazepam. Notwithstanding the reduced efficacy, darigabat is effective in the pentylenetetrazol and amygdala kindling rodent seizure models, and also the GAERS genetic rat model of absence seizures (Duveau et al., 2018). In a human trial, darigabat exhibited activity against light-evoked seizures in photosensitive epilepsy (Gurrell et al., 2019). Whether darigabat will have less propensity for tolerance than nonselective, full benzodiazepine receptor-positive modulators remains to be determined. However, the fact that it has low efficacy at α1 and α2 suggests a reasonable likelihood that this could be the case. KRM-II-81 differs from darigabat in that it binds with low affinity to α1 but has high affinity for α3, α2, and α5; it is inactive at α4 and α6 (Knutson et al., 2020; Cerne et al., 2021). It is representative of other novel selective benzodiazepine-site modulators that could find appliction in epilepy therapy.

As noted above, the 1,5-benzodiazepine clobazam is used commonly in the chronic treatment of epilepsy as it may be better tolerated and less subject to tolerance than conventional 1,4-benzodiazepines (Haigh et al., 1987). Clobazam itself is a nonselective positive GABAR modulator as are diazepam and other clinically used 1,4-benzodiazepines. However, clobazam’s major active metabolite N-desmethyl-clobazam (norclobazam) while having similar potency at α1 and α2 GABAR, in some but not all studies, exhibited greater maximal efficacy at α2 (Hammer et al., 2015; Ralvenius et al., 2016), thus raising the possibility of a degree of α2 selectivity. Norclobazam has greater stability in plasma than clobazam (t_½, 79 h vs. 36 h) so that with chronic dosing the levels of the metabolite exceed that of the parent (Kinoshita et al., 2007). Whether the improved tolerability and reduced propensity for tolerance of clobazam relates to the α2 selectivity of norcloabazam remains to be determined.

Treatment of Epilepsy Comorbidities

Targeting GABAR subtypes may not only provide greater tolerability but could also theoretically provide a means to treat epilepsy comorbidities, including autistic behaviors, cognitive impairment, and depression. Dravet syndrome, an early-onset DEE, is most commonly caused by mutations in SCN1A that result in haploinsufficiency of the Nav1.1 voltage-activated sodium channel. Children with the disorder have cognitive deficits and an increased incidence of autistic behaviors. Mice with a heterozygous loss-of-function mutation in Scn1a (Scn1a^+/−) have also been found to exhibit autistic-like behaviors, including hyperactivity, stereotypies, social interaction deficits, and impaired fear conditioning (Han et al., 2012). In Scn1a^+/− mice, treatment with the benzodiazepine clonazepam, a positive allosteric modulator of synaptic GABARs, reversed the social interaction and fear conditioning deficits at doses below those causing sedative or anxiolytic effects. While these results suggest that GABAR modulators could reduce autistic behaviors in Dravet syndrome, this has not yet been confirmed in clinical studies.

GABAR α5-subunit-containing receptors, which are primarily expressed in the hippocampus, are known to play a modulatory role in learning and memory (Martin et al., 2010; Rudolph and Knoflach, 2011). Activation of these receptors is believed to be a major factor in the amnestic effects of anesthetics (Wang and Orser, 2011). Conversely, selective GABAR α5 negative allosteric modulators have been found to exhibit cognitive enhancing properties without the well-recognized anxiogenic and proconvulsant effects produced by nonselective GABAR blockers (Olsen, 2018; Jacob, 2019). Negative allosteric modulators of α5 GABARs have also been found to have antidepressant-like effects (Fischell et al., 2015; Zanos et al., 2017; Xu et al., 2018). Consequently, GABAR α5 negative allosteric modulators could benefit two of the key epilepsy comorbidities (see Chapters 57 and 61, this volume), while avoiding the risk of worsening seizures that would be present with nonselective GABAR inhibitors.

EtOH-Induced Plasticity of GABAR-Mediated Inhibition at the Gene Expression and Protein Levels

Experience and activity are known to modify GABAR expression. An example is provided by the chronic intermittent ethanol (CIE) rodent model of alcohol use disorder in which plasticity in GABAR subtype expression has physiological and pharmacological consequences. In the model, animals exhibit transitory increased anxiety and rapid down-regulation of GABAR δ-subunit protein after ethanol administration (Cagetti et al., 2003), with the increased anxiety and hyperexcitability becoming persistent after multiple episodes of intoxication and withdrawal, representing a kindling-like phenomenon (Olsen and Liang, 2017; Olsen and Spigelman, 2012). Kindling-like effects in the CIE model were associated with hypofunction of GABARs in the hippocampus (Kang et al., 1996; Basu and Suh, 2020). Following sudden alcohol withdrawal, α4-subunit mRNA expression increased so that synaptic α1 receptors may be transformed from benzodiazepine sensitivity to insensitivity by virtue of inclusion of α4 (Liang et al., 2004). A similar upregulation of α4-subunits has been observed in several animal models of temporal lobe epilepsy (Olsen and Spigelman, 2012). Therefore, it has been proposed that elevated levels of GABAR α4-subunits may be associated with alcohol withdrawal seizure risk. Similar alterations in GABAR-subunit composition were observed in the basolateral amygdala during the withdrawal phase of CIE: α4 and γ2 surface expression increased, while α1, α2, and δ decreased (Lindemeyer et al., 2014). This was associated with enhanced sensitivity of synaptic GABAR currents to ethanol and faster mIPSC decay, which could relate to reduced GABAR-mediated synaptic inhibition and propensity for seizures. A decrease in extrasynaptic δ-subunit-containing GABARs results in a reduced ability of ethanol to potentiate tonic GABAR currents. δ GABARs have been proposed as the key target mediating behavioral responses to low doses of ethanol (Hanchar et al., 2005, Wallner et al., 2014), and a reduction in these ethanol-sensitive receptors may be critical for ethanol tolerance (Olsen et al., 2007).

Complex changes in GABAR expression also occur in the hippocampus after acute ethanol intoxication and CIE (Lindemeyer et al., 2017). As in the amygdala, there is upregulation of α4-subunits. In addition, there are increased cell-surface levels of GABAR α2-subunits, raising the possibility that the α2-selective GABAR positive modulators discussed above could be of value in treating ethanol withdrawal, including ethanol withdrawal seizures.

Synaptic Matrix Tethering with Neuroligin-2, Gephyrin, and Collybistin; Role of LHFPL4

The recruitment of GABARs to the postsynaptic membrane requires the scaffold protein gephyrin and the guanine nucleotide exchange factor collybistin (Fritschy et al., 2012; Tyagarajan and Fritschy, 2014; Papadopoulos et al., 2017). Neuroligin-2, a cell adhesion protein specifically located to inhibitory synapses that binds to presynaptic neurexin (Ali et al., 2020), also contributes to tethering GABARs. Alterations in these proteins may be pathogenic in some forms of epilepsy.

Loss of gephyrin has been observed in animal models of temporal lobe epilepsy (Kumar and Buckmaster, 2006), and pathological gephyrin expression has been identified in the hippocampi of patients with temporal lobe epilepsy (Förstera et al., 2010). In the latter study with human patient samples, no gephyrin gene mutations were observed. Instead, the investigators found aberrant alternative gephyrin splice variants lacking several exons in their G-domains, which exhibited pathological dominant negative effects on normal hippocampal gephyrin. More recent studies have found missense mutations in the gephyrin gene, which are believed to be pathogenic (Dejanovic et al., 2015; Lionel et al., 2013). The heterozygous missense mutation G375D has been extensively studied and found to disrupt binding of gephyrin to GABARs and neuroligin-2 (Dejanovic et al., 2015; Kim et al., 2021). Neuroligin-2 itself may play a pathological role in epilepsy. To date, neuroligin-2 variants have been associated with autism and other neurodevelopment disorders but not specifically epilepsy. However, in a recent study neuroligin-2 knockout mice exhibited absence-like seizures that were inhibited by the antiabsence drug exthosuximide (Cao et al., 2020).

Disrupting the interaction between collybistin and α2 GABARs with a mutation in the α2-subunit’s collybistin binding region (Gabra2-1), caused a loss of inhibitory synapses in mice bearing the mutation (Hines et al., 2018). The mice also exhibited increased seizure susceptibility and early mortality. Augmenting the synaptic targeting of α1 GABARs with a mutation that strengthened interactions between the receptor and collybistin increased inhibitory neurotransmission (Nathanson et al., 2019). This mutation reduced the severity of kainate-induced seizures and also rescued mice with the Gabra2-1 mutation so that they no longer exhibited early mortality. Alterations in the various proteins that recruit GABARs to synaptic membranes could potentially represent pathogenic mechanisms in epilepsy while an understanding of the mechanisms for recruitment could suggest treatment approaches.

An example of a potential disease mechanism has been provided by Papadopoulos et al. (2015). These investigators identified patients with epilepsy and intellectual disability that have an R290H missense mutation in the diffuse B-cell lymphoma homology domain of collybistin, which carries the guanine nucleotide exchange factor activity (Papadopoulos et al., 2015). The mutation alters the strength of intramolecular interactions between the diffuse B-cell lymphoma homology domain and the pleckstrin homology domain of collybistin. The pleckstrin homology domain of collybistin specifically binds to phosphatidylinositol 3-phosphate (PI3P), which is believed to be essential for anchoring complexes containing gephyrin, neuroligin-2, and collybistin to the postsynaptic membrane. The mutation was found to reduce the PI3P binding affinity of collybistin and limit GABAergic synapse development. A deficiency in the recruitment of GABARs to the postsynaptic membrane of inhibitory synapses is a plausible mechanism for the epilepsy and mental retardation in subjects with the R290H mutation.

The tetraspanin protein LHFPL4, also referred to as GARLH4, is also critical to the development of GABAergic synapses and is potentially relevant to epileptogenesis. Davenport et al. (2017) identified LHFPL4 as a membrane protein selectively enriched at inhibitory synapses that interacts tightly with GABAR subunits. LHFPL4 is required for surface clustering but not trafficking of GABAR in hippocampal CA1 pyramidal neurons (Yamasaki et al., 2017). LHFPL4 is therefore essential for inhibitory synapse function. Deletion of LHFPL4/GARLH4 in mice results in impaired inhibitory synapse formation (Wu et al., 2018). Such Lhfpl4/Garlh4^−/− knockout mice have cerebellum-related motor deficits, increased pentylenetetrazol seizure susceptibility, and premature death.

Activation of Extrasynaptic δ-GABAR Induces Spike-Wave Seizures

Muscimol, the psychoactive substance in Amanita muscaria, and its conformationally constrained derivative gaboxadol [4,5,6,7- tetrahydroisoxazolo(5,4-c)pyridin-3-ol; THIP], structurally resemble GABA, and like GABA, they are exceptionally potent as direct activators of extrasynaptic GABAR containing the δ-subunit (Meera et al., 2011; Benkherouf et al., 2019). Indeed, there is drastically reduced high-affinity (6 nM) [³H]muscimol binding in the brains of δ-subunit knockout mice (Mihalek et al., 1999). Low-dose THIP and muscimol are expected to preferentially activate GABAR δ so that the relatively rare GABAR δ receptor subtypes (about 5%–10% of total GABAR) are of particular importance to their biochemical and behavioral actions (Chandra et al., 2006, 2010; Mäkelä et al., 1997; Beaumont et al., 1978). Given the role of extrasynaptic GABAR δ in tonic inhibition, THIP and muscimol might be expected to reduce circuit excitability and have antiseizure properties. However, these agonists are not effective antiseizure agents in focal seizure models (Löscher and Schwark, 1985). Moreover, in normal rodents, THIP induces both behavioral and electrographic spike-wave seizures (Fariello and Golden, 1987; Snead, 1992). In addition to the ability of pharmacological activation of extrasynaptic GABAR to induce such absence-like seizures, there is evidence of enhanced extrasynaptic GABAR-dependent tonic inhibition in thalamocortical neurons in diverse genetic and pharmacological models of absence seizures (Cope et al., 2009). This could be due to increased GABAR δ expression and/or increased extracellular GABA. In contrast, decreased δ-subunit expression has been observed in other epilepsy models (Peng et al., 2004; Schwarzer et al., 1997), as well as in the CIE model of alcohol use disorder, which shows increased seizure susceptibility (Olsen and Spigelman, 2012). How extrasynaptic GABAR activation predisposes to spike-wave seizures is not well understood. One hypothesis is that highly THIP-sensitive extrasynaptic GABAR containing δ-subunits are expressed on GABAergic interneurons that silence projection neurons in the thalamocortical network so that THIP disinhibits the thalamocortical network. Indeed, THIP prominently activates tonic current in GABAergic interneurons, reducing inhibitory neurotransmission (Drasbek and Jensen, 2006; Lee and Maguire, 2014; Field et al., 2021). A second possibility is that enhanced tonic current hyperpolarizes relay neurons sufficiently to disinhibit low-threshold T-type calcium channels, causing the thalamocortical circuit to transition from the tonic to phasic firing that underlies spike-wave seizure activity (Suzuki and Rogawski, 1989; Sorokin et al., 2017).

Advances in GABAR Structural Pharmacology Relevant to Pentobarbital, Propofol, and Etomidate

The intravenous anesthetics pentobarbital, propfol, and etomidate produce large enhancement of GABA-induced GABAR currents and also directly activate the receptors, conferring them with powerful antiseizure activity (Hales and Lambert, 1991; ffrench-Mullen et al., 1993; Rho et al., 1996; Löscher and Rogawski, 2012). These modulators bind to subunit interfaces within transmembrane regions (Eaton et al., 2016; Chiara et al., 2016).

Recent studies using cryo-electron microscopy (cryo-EM) of GABARs in lipid nanodiscs that mimic neuronal membranes have revealed new structural details on subunit architecture and assembly; the location of binding sites for modulatory ligands; and the conformational changes initiated by binding of ligands including picrotoxin, bicuculline, alprazolam, and diazepam, with and without GABA (Olsen et al., 2019; Laverty et al. 2019; Masiulis et al., 2019). The cryo-EM structure of the human α1β3γ2 GABAR (Laverty et al., 2019) show bound endogenous PIP2 attached to the GABAR α1-subunit (see Fig. 48–1) where it could modulate channel function (Hille et al., 2015). Phosphoinositides like PIP2 have been implicated in many cellular functions including the synaptic localization of GABARs (Papadopoulos et al., 2017). Similarly, GABARAP (GABAR associated protein), a ubiquitin-like protein required for the formation of autophagosomal membranes which binds to the intracellular loop of γ2 GABARs (Ohsumi, 2001; Ye et al., 2021), is involved in GABAR trafficking (Wang et al, 1999). Such regulatory trafficking systems may play a role in epilepsy pathogenesis and could be a target for therapeutic interventions.

Figure 48–1.

Cryo-EM structure of the α1β3γ2 GABA receptor a) view from the extracellular space and b) transmembrane orientation (modified from Masiulis et al., 2019). Dashed box (B,C) indicates high affinity diazepam (DZP) binding site at (more...)

Recently, co-crystal structures of the three anesthetics phenobarbital, propofol, and etomidate were solved using cryo-EM (see Fig. 48–2) (Kim et al., 2020). Two phenobarbital sites were resolved in the cryo-EM images in the transmembrane domain (TMD), one at the α1_B+/β2_C- subunit interface and the other at the γ2_E+/β2_C- subunit interface. It was shown that both etomidate and propofol share a common binding pocket at the α1+/β2- transmembrane subunit interfaces, with the β2,3N265 residue (in TMD2) and βM286 (in TMD3) lining the binding pocket (see Fig. 48–2). The β2/3N265M mutation was shown to render receptors insensitive to etomidate and propofol (Belelli et al., 1997; Siegwart et al., 2002). This point mutation was introduced into mice by knock-in gene targeting. Mice carrying the etomidate/propofol-insensitive β3N265M point mutation were nearly completely resistant to the hypnotic, immobilizing, and anesthetic actions of propofol and etomidate (Jurd et al., 2003). In contrast, mutation of the homologous residue in the β2-subunit caused loss of only the sedative effects of the anesthetics (Reynolds et al., 2003). Mice bearing an etomidate-insensitive β2-subunit (β2 N265S) could be anesthetized as indicated by limb withdrawal and burst suppression in the EEG, but etomidate did not cause sedation in these animals. There are two possible explanations for the separation of anesthetic and sedative etomidate and propofol effects. First, since classical synaptic α1β2γ2-subunits make up almost 50% of total brain receptors and β2-subunits are almost 50% of total β receptors (β1 is rare) (Whiting, 2003), most β2- (and also α1-) subunits are harbored in α1β2γ2 GABARs, which likely mediate sedative diazepam effects, as shown with α1H101R knock-in mice (Rudolph et al., 1999). By extension, β3- and β1-subunits should be found mostly in other (non-α1β2γ2) receptors, including extrasynaptic subtypes. Second, GABAR β2- and β3-subunits could be expressed in different circuits that mediate anesthetic (β3) and sedative (β2) actions (Engin et al., 2018; Grasshoff et al., 2007). For example, β3-subunit-containing GABARs in the spinal cord likely mediate hindlimb withdrawal reflexes that are suppressed by etomidate and propofol in wild-type but not in β3N265M mice (Jurd et al., 2003). The most likely subunit composition of spinal cord GABARs involved in the immobilizing actions of etomidate and propofol can be assumed to be α2/3β3γ2 (Grasshoff et al., 2006).

Figure 48–2.

Phenobarbital and propofol (etomidate) binding sites in GABAR transmembrane regions (modified from Kim et al., 2020).

The β3N265M and β3M268W mutations also reduced the GABA-enhancing effects of the volatile anesthetic enflurane when recombinantly expressed with α1 and β2 receptors (Siegwart et al., 2002). Behavioral analysis of β3N265M knock-in mice suggests that β3-containing GABAR make minor, yet significant, contributions to the actions of the volatile anesthetics enflurane and halothane (Zeller et al., 2007; Jurd et al., 2003; Antkowiak and Rudolph, 2016).

Neuroactive Steroids

The neuroactive steroid ganaxolone, the 3β-methyl analog of the endogenous neurosteroid allopregnanolone (Carter et al., 1997), is the first such steroid approved for epilepsy treatment. Like allopregnanolone, ganaxolone has antiseizure activity in a broad range of animal models (Reddy and Rogawski, 2012). As is the case for propofol, etomidate, and enflurane, neuroactive steroids also produce their effects on GABARs by binding to sites within transmembrane regions. The TMD of the α-subunits have been found to be of particular importance for neuroactive steroid binding in contrast to the situation for the anesthetics where mutations in the β-subunits were found to eliminate activity. To date, three distinct binding sites for potentiating neuroactive steroids have been identified in GABARs (Wang et al., 2022). The sites are located at the β+/α–-subunit interface (site I) and within the α- (site II) and β- subunits (site III) (Chen et al., 2019). A recent study indicates that the sites act independently and additively (Germann et al., 2021). Site I is the oldest and best characterized (Hosie et al., 2006, 2009). Mutagenesis studies in α1β2γ2 GABARs identified αQ241 (rat, equivalent to αQ242 in human) in TMD1 as within this canonical site for neuroactive steroid potentiation. Recent results from X-ray crystallography have shown that in homo-pentameric chimeric receptors in which the TMDs are derived from either α1- or α5-subunits, neuroactive steroids bind in a cleft between the α-subunits, with the steroid A-ring C3 α-hydroxyl group interacting directly with α1Q241 (Laverty et al., 2017; Miller et al., 2017). In these studies, α1Q241L and α1Q241W mutations eliminated neuroactive steroid modulation. Neuroactive steroids positively modulate all GABAR isoforms, benzodiazepine-sensitive and benzodiazepine-insensitive. Interaction of the steroids with Q241 in α-subunits is responsible for the broad activity. Middle-down mass spectrometry has allowed identification of Site II and Site III, which had not previously been characterized (Chen et al., 2019). Site II is within a cavity between the extracellular ends of the TMD1 and TMD4 segments of the α-subunit. Site III is located between the TMD3 and TMD4 segments of the β-subunit. Electrophysiological studies have shown that binding to Sites I and II contributes to potentiation by allopregnanolone, whereas binding to Site III does not (Chen et al., 2019; Germann et al., 2021). Recent cryo-EM studies with molecular dynamics simulations have revealed how binding of allopregnanolone to Site I at the β+/α- subunit interface induces positive modulation of the GABAR (Legesse et al., 2023; Sun et al., 2023. These studies confirm that the steroid A-ring C3 α-hydroxyl group of allopregnanolone forms a hydrogen bond with αQ242 (human) whereas the C20 ketone on the steroid D-ring is oriented toward and forms a hydrophobic interaction with the β-subunit L301. The studies further demonstrate that the presence of allopregnanolone in its β+/α- subunit interface binding pocket influences the conformational state and dynamics of the GABAR to stabilize the transmembrane domain open-channel conformation, reduce GABA dissociation, and induce apical pore dilation so as to reduce the energy barrier for chloride flux through the channel.

Benzodiazepines

The binding site for classical benzodiazepines is at the interface between the α (1,2,3,5)- and γ2-subunits in the receptor’s extracellular domain. Several histidine residues (α1H101, α2H101, α3H126, α5H105) are critical for sensitivity to classical benzodiazepines, such as diazepam (see Fig. 48–1; note that mouse α1H01 corresponds to human α1H102). The insensitivity of the α4- or α6-subunits to classical benzodiazepines can be attributed to replacement of the N-terminal histidine (H101) residue of the α1-, α2-, α3-, and α5-subunits by an arginine residue in α4 and α6. The importance of these sites for the in vivo pharmacological actions of benzodiazepines has been demonstrated by gene targeting in which α1H101R knock-in mice fail to exhibit sedative diazepam actions (Rudolph et al., 1999) and α2H101R knock-in mice fail to exhibit anxiolytic diazepam actions (Löw et al., 2000; Rudolph and Möhler, 2004). Besides the high-affinity sites for benzodiazepines at the α/γ2-subunit interface, GABARs also posses a low-affinity benzodiazepine binding site. Diazepam actions at the low-affinity site require almost 1000 times (EC₅₀ ~ 20–100 μM) higher concentrations than at the high-affinity site (EC₅₀ ~ 100 nM). Unlike positive modulation at the high-affinity site, enhancement of GABAR function by high diazepam concentrations is not dependent on the presences of a γ2-subunit, and also not reversed by the clinically used benzodiazepine antagonist flumazenil (Walters et al., 2000; Wang et al., 2021b). Both high- and low-affinity diazepam sites have been recently resolved in cryo-EM structures (see Fig. 48–1). Identification of the high-affinity diazepam binding pocket using this methodology confirms many years of work mapping this site at the α+/γ2-extracellular domain by mutational analysis and photoaffinity labeling (Kleingoor et al., 1991; Sawyer et al., 2002; Li et al., 2009; Sigel and Ernst, 2018). It is noteworthy that the low-affinity diazepam site identified by cryo-EM at the α+β-transmembrane interface shown in Figure 48–1 shares an overlapping binding pocket with the propofol and etomidate binding sites (shown in Fig. 48–2) despite the dissimilar molecular structures of the ligands. The clinical significance of the low-affinity flumazenil-insensitive site is uncertain. Like diazepam, midazolam positively modulates GABARs in a flumazenil-insensitive manner at high concentrations (200 μM or 65,000 ng/ml) (Wang et al., 2021b). Midazolam is often used at high doses for the treatment of acute seizures, including status epilepticus (Crawshaw and Cock, 2020), raising the question of whether binding to the low-affinity site is relevant in these situations. However, at doses used in the treatment of status epilepticus and even with toxicological doses causing respiratory depression, cerebrospinal fluid and brain concentrations are only in the range of 500–800 ng/ml (Arendt et al., 1983; Megarbane et al., 2005; Zolkowska et al., 2021) and are too low to interact with the low–affinity binding site.

Stiripentol

Stiripentol, an α-ethylene alcohol approved for the treatment of seizures associated with Dravet syndrome, is a modestly efficacious positive allosteric modulator of synaptic and extrasynaptic GABARs (Fisher, 2009; Sills and Rogawski, 2020). α3-containing GABARs, which are prominent in the developing brain, exhibit a larger potentiation than those composed of other α-subunits, perhaps accounting for stiripentol’s preferential clinical utility in childhood epilepsy syndromes. Stiripentol extends the duration of chloride channel opening in response to synaptically released GABA in a manner similar to that observed with barbiturates (Quilichini et al., 2006). Indeed, a recent study indicated that stiripentol binds with high affinity to the GABAR γ+/β- and α+?-β- interfaces as do barbiturates (Jayakar et al., 2019).

Optogenetics and Chemogenetics

GABAR antagonists, agonists, and modulators have a long history as tools to assess the physiological roles of the receptors in diverse neural circuits. In the future, the tool kit will be expanded with chemogenetic and optogenetic approaches that will allow greater definition of the roles of subsets of receptors, defined either by their specific localization or subunit composition, or both (Walker and Kullmann, 2020). For example, GABARs that can be shut off by light have been created by conjugating a photoswitchable tethered small molecule ligand onto a modified GABAR α-subunit (LiGABAR), which can be expressed in vivo using a viral vector or by knock-in technology (Lin et al., 2015). LiGABARs can be used to photo-control specific GABAR isoforms or geographically localized populations of GABAR, or to independently control synaptic or extrasynaptic receptors. In the future such approaches could be applied therapeutically (see Chapter 77, this volume).

Conclusion and Future Directions

GABARs are pivotal to the excitability mechanisms critical to seizures and epilepsy. Loss of GABA interneurons has long been believed to be a key pathogenic mechanism in some forms of epilepsy (Houser, 2014). At the time of publication of the prior edition of this book, it had been recognized that along with the interneuron loss, there is morphological reorganization of remaining interneurons and compensatory upregulation of GABARs. Such changes have been observed in various epilepsy models and also in tissue from patients with temporal lobe epilepsy (Loup et al., 2000a, 2000b; Pirker, 2003; Möhler, 2006; Houser et al., 2012). The significance of these changes is incompletely understood and will continue to be studied. Epilepsy-causing mutations that had been identified at that time were mainly in large families with childhood absence epilepsy, febrile seizures (GEFS+), and juvenile myoclonic epilepsy (Cossette et al., 2012; Petrou and Reid, 2012; Macdonald et al., 2012). It is now recognized that pathogenic variants in these genes are infrequent (Chapter 41, this volume). In the last decade, there has been increasing recognition that de novo variants in GABAR genes are pathogenic in certain severe early-onset DEEs. Investigation of the ways in which GABAR variants lead to diverse epilepsies and associated comorbidities will be a research topic in the next decade.

GABAR isoforms are key targets for antiseizure medications used to treat acute seizure emergencies and in the chronic treatment of epilepsy. The investigation of such agents is continuing, with current attention on selective α2,α3 GABAR-positive allosteric modulators with various degrees of partial agonist activity (Witkin et al., 2018; Cerne et al., 2021). Several such modulators are in clinical development. There is also continuing interest in neuroactive steroids like ganaxolone that act as GABAR-positive allosteric modulators. At the same time that traditional pharmacological approaches continue to be pursued, the wealth of new information on the physiological and cell biological consequences of epilepsy-associated GABAR gene variants provide opportunities for genetic therapies that could be more effective than traditional pharmacological approaches. Such therapies may treat comorbidities, and if they permanently correct mutations, which is possible, for example, with gene editing (Chapter 76, this volume), they could be curative. It can be expected that many different approaches will be evaluated in the coming decade. In some situations, strategies that affect the functional activity or the membrane expression of subpopulations of wild-type GABARs may provide the desired therapeutic effect. Where the disease phenotype is due to a dominant negative or toxic effect of the mutant protein, disease correction may require an approach that eliminates the production of mutant protein, such as with RNA interference or with small molecules that promote the disposal of the mutant protein (Kang and Macdonald, 2016). In cases where there is a reduced abundance of synaptic GABARs and also a toxic effect of the mutant receptor, a combined therapeutic strategy may be necessary in which increased expression of wild-type GABARs is supplemented with an approach that reduces expression of the mutant form. For each specific disease-causing variant, the pathogenic mechanisms will need to be defined to select the most appropriate therapy for the affected patient. This appears to be a daunting challenge, but methods to characterize the functional effects of mutations can be expected to become more efficient in the years to come. Continuing advances in gene therapy approaches to correct genetic defects or influence ion channel expression suggest that the creation of highly specific gene therapies will become routine (see Chapters 76 and 77, this volume). These developments engender optimism that personalized therapies for the diverse epilepsies caused by GABAR variants are achievable.

Disclosure Statement

References

1. Absalom NL, Liao VWY, Johannesen KMH, Gardella E, Jacobs J, Lesca G, Gokce-Samar Z, Arzimanoglou A, Zeidler S, Striano P, Meyer P, Benkel-Herrenbrueck I, Mero IL, Rummel J, Chebib M, Møller RS, Ahring PK. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies.  Nat Commun. 2022 May 24;145(4):1299-1309. doi: 10.1093/brain/awab391. PMID: 34633442; PMCID: PMC9630717. [PMC free article: PMC8983652] [PubMed: 35383156]
2. Ahring PK, Liao VWY, Gardella E, Johannesen KM, Krey I, Selmer KK, Stadheim BF, Davis H, Peinhardt C, Koko M, Coorg RK, Syrbe S, Bertsche A, Santiago-Sim T, Diemer T, Fenger CD, Platzer K, Eichler EE, Lerche H, Lemke JR, Chebib M, Møller RS.  Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy.  Brain. 2022 May 24;145(4):1299–1309. doi: 10.1093/brain/awab391. PMID: 34633442; PMCID: PMC9630717. [PMC free article: PMC9630717] [PubMed: 34633442]
3. Ali H, Marth L, Krueger-Burg D.  Neuroligin-2 as a central organizer of inhibitory synapses in health and disease.  Sci Signal. 2020 Dec 22;13(663):eabd8379. doi: 10.1126/scisignal.abd8379. PMID: 33443230. [PubMed: 33443230]
4. Antkowiak B, Rudolph U. New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors. Curr Opin Anaesthesiol. 2016 Aug;29(4):447–53. doi: 10.1097/ACO.0000000000000358. PMID: 27168087; PMCID: PMC4957807. [PMC free article: PMC4957807] [PubMed: 27168087]
5. Arendt RM, Greenblatt DJ, deJong RH, Bonin JD, Abernethy DR, Ehrenberg BL, Giles HG, Sellers EM, Shader RI.  In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.  J Pharmacol Exp Ther. 1983 Oct;227(1):98–106. PMID: 6137558. [PubMed: 6137558]
6. Atack JR, Hallett DJ, Tye S, Wafford KA, Ryan C, Sanabria-Bohórquez SM, Eng WS, Gibson RE, Burns HD, Dawson GR, Carling RW, Street LJ, Pike A, De Lepeleire I, Van Laere K, Bormans G, de Hoon JN, Van Hecken A, McKernan RM, Murphy MG, Hargreaves RJ. Preclinical and clinical pharmacology of TPA023B, a GABA_A receptor α2/α3 subtype-selective partial agonist. J Psychopharmacol. 2011 Mar;25(3):329–44. doi: 10.1177/0269881109354928. Epub 2010 Feb 15. PMID: 20156926. [PubMed: 20156926]
7. Atack JR, Wafford KA, Tye SJ, Cook SM, Sohal B, Pike A, Sur C, Melillo D, Bristow L, Bromidge F, Ragan I, Kerby J, Street L, Carling R, Castro JL, Whiting P, Dawson GR, McKernan RM. TPA023 [7-(1,1- dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABA_A receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther. 2006 Jan;316(1):410–22. doi: 10.1124/jpet.105.089920. Epub 2005 Sep 23. PMID: 16183706. [PubMed: 16183706]
8. Auta J, Giusti P, Guidotti A, Costa E. Imidazenil, a partial positive allosteric modulator of GABA_A receptors, exhibits low tolerance and dependence liabilities in the rat. J Pharmacol Exp Ther. 1994 Sep;270(3):1262–9. PMID: 7932179. [PubMed: 7932179]
9. Auta J, Impagnatiello F, Kadriu B, Guidotti A, Costa E. Imidazenil: a low efficacy agonist at α1- but high efficacy at α5- GABA_A receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem. Neuropharmacology. 2008 Aug;55(2):148–53. doi: 10.1016/j.neuropharm.2008.05.002. Epub 2008 May 9. PMID: 18555494; PMCID: PMC2601598. [PMC free article: PMC2601598] [PubMed: 18555494]
10. Basu S, Suh H.  Role of hippocampal neurogenesis in alcohol withdrawal seizures.  Brain Plast. 2020 Dec 29;6(1):27–39. doi: 10.3233/BPL-200114. PMID: 33680844; PMCID: PMC7903005. [PMC free article: PMC7903005] [PubMed: 33680844]
11. Beaumont K, Chilton WS, Yamamura HI, Enna SJ. Muscimol binding in rat brain: association with synaptic GABA receptors. Brain Res. 1978 Jun 9;148(1):153–62. doi: 10.1016/0006-8993(78)90385-2. PMID: 207386. [PubMed: 207386]
12. Belelli D, Harrison NL, Maguire J, Macdonald RL, Walker MC, Cope DW. Extrasynaptic GABA_A receptors: form, pharmacology, and function. J Neurosci. 2009 Oct 14;29(41):12757–63. doi: 10.1523/JNEUROSCI.3340-09.2009. PMID: 19828786; PMCID: PMC2784229. [PMC free article: PMC2784229] [PubMed: 19828786]
13. Belelli D, Lambert JJ, Peters JA, Wafford K, Whiting PJ. The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11031–6. doi: 10.1073/pnas.94.20.11031. PMID: 9380754; PMCID: PMC23576. [PMC free article: PMC23576] [PubMed: 9380754]
14. Benkherouf AY, Taina KR, Meera P, Aalto AJ, Li XG, Soini SL, Wallner M, Uusi-Oukari M. Extrasynaptic δ- GABA_A receptors are high-affinity muscimol receptors. J Neurochem. 2019 Apr;149(1):41–53. doi: 10.1111/jnc.14646. Epub 2019 Mar 6. PMID: 30565258; PMCID: PMC6438731. [PMC free article: PMC6438731] [PubMed: 30565258]
15. Bernard C.  2012. Alterations in synaptic function in epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 470–483.
16. Bouilleret V, Loup F, Kiener T, Marescaux C, Fritschy J-M. Early loss of interneurons and delayed subunit-specific changes in GABA_A -receptor expression in a mouse model of mesial temporal lobe epilepsy. Hippocampus.  2000b;10(3):305–24. doi: 10.1002/1098-1063(2000)10:3<305::AID-HIPO11>3.0.CO;2-I. PMID: 10902900. [PubMed: 10902900]
17. Brandon NJ, Delmas P, Kittler JT, McDonald BJ, Sieghart W, Brown DA, Smart TG, Moss SJ. GABA_A receptor phosphorylation and functional modulation in cortical neurons by a protein kinase C-dependent pathway. J Biol Chem.  2000 Dec 8;275(49):38856–62. doi: 10.1074/jbc.M004910200. PMID: 10978327. [PubMed: 10978327]
18. Brooks-Kayal AR, Russek SJ. Regulation of GABA_A receptor gene expression and epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 574–580.
19. Cagetti E, Liang J, Spigelman I, Olsen RW. Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABA_A receptors. Mol Pharmacol. 2003 Jan;63(1):53–64. doi: 10.1124/mol.63.1.53. PMID: 12488536. [PubMed: 12488536]
20. Cao F, Liu JJ, Zhou S, Cortez MA, Snead OC, Han J, Jia Z.  Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry.  Nat Commun. 2020 Jul 27;11(1):3744. doi: 10.1038/s41467-020-17560-3. PMID: 32719346; PMCID: PMC7385104. [PMC free article: PMC7385104] [PubMed: 32719346]
21. Carter RB, Wood PL, Wieland S, Hawkinson JE, Belelli D, Lambert JJ, White HS, Wolf HH, Mirsadeghi S, Tahir SH, Bolger MB, Lan NC, Gee KW. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ- aminobutyric acidA receptor. J Pharmacol Exp Ther. 1997 Mar;280(3):1284–95. PMID: 9067315. [PubMed: 9067315]
22. Carvill GL, Weckhuysen S, McMahon JM, Hartmann C, Møller RS, Hjalgrim H, Cook J, Geraghty E, O’Roak BJ, Petrou S, Clarke A, Gill D, Sadleir LG, Muhle H, von Spiczak S, Nikanorova M, Hodgson BL, Gazina EV, Suls A, Shendure J, Dibbens LM, De Jonghe P, Helbig I, Berkovic SF, Scheffer IE, Mefford HC.  GABRA1 and STXBP1: novel genetic causes of Dravet syndrome.  Neurology. 2014 Apr 8;82(14):1245–53. doi: 10.1212/WNL.0000000000000291. Epub 2014 Mar 12. PMID: 24623842; PMCID: PMC4001207. [PMC free article: PMC4001207] [PubMed: 24623842]
23. Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, Golani LK, Cook JM, Witkin JM. GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABA_A receptors. Pharmacol Ther. 2021 Nov 16:108035. doi: 10.1016/j.pharmthera.2021.108035. Epub ahead of print. PMID: 34793859. [PMC free article: PMC9787737] [PubMed: 34793859]
24. Chandra D, Halonen LM, Linden AM, Procaccini C, Hellsten K, Homanics GE, Korpi ER. Prototypic GABA_A receptor agonist muscimol acts preferentially through forebrain high-affinity binding sites. Neuropsychopharmacology. 2010 Mar;35(4):999–1007. doi: 10.1038/npp.2009.203. Epub 2009 Dec 23. PMID: 20032968; PMCID: PMC2823376. [PMC free article: PMC2823376] [PubMed: 20032968]
25. Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL, Homanics GE. GABA_A receptor α4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15230–5. doi: 10.1073/pnas.0604304103. Epub 2006 Sep 27. PMID: 17005728; PMCID: PMC1578762. [PMC free article: PMC1578762] [PubMed: 17005728]
26. Chen ZW, Bracamontes JR, Budelier MM, Germann AL, Shin DJ, Kathiresan K, Qian MX, Manion B, Cheng WWL, Reichert DE, Akk G, Covey DF, Evers AS. Multiple functional neurosteroid binding sites on GABA_A receptors. PLoS Biol. 2019 Mar 7;17(3):e3000157. doi: 10.1371/journal.pbio.3000157. PMID: 30845142; PMCID: PMC6424464. [PMC free article: PMC6424464] [PubMed: 30845142]
27. Cheng T, Wallace DM, Ponteri B, Tuli M. Valium without dependence? Individual GABA_A receptor subtype contribution toward benzodiazepine addiction, tolerance, and therapeutic effects. Neuropsychiatr Dis Treat. 2018 May 23;14:1351–1361. doi: 10.2147/NDT.S164307. PMID: 29872302; PMCID: PMC5973310. [PMC free article: PMC5973310] [PubMed: 29872302]
28. Cherubini E. Phasic GABA_A-mediated inhibition. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 97–110.
29. Chiara DC, Jounaidi Y, Zhou X, Savechenkov PY, Bruzik KS, Miller KW, Cohen JB. General anesthetic binding sites in human α4β3δ γ-aminobutyric acid type A receptors (GABA_A Rs). J Biol Chem. 2016 Dec 16;291(51):26529–26539. doi: 10.1074/jbc.M116.753335. Epub 2016 Nov 7. PMID: 27821594; PMCID: PMC5159512. [PMC free article: PMC5159512] [PubMed: 27821594]
30. Cope DW, Di Giovanni G, Fyson SJ, Orbán G, Errington AC, Lorincz ML, Gould TM, Carter DA, Crunelli V. Enhanced tonic GABA_A inhibition in typical absence epilepsy. Nat Med. 2009 Dec;15(12):1392–8. doi: 10.1038/nm.2058. Epub 2009 Nov 22. PMID: 19966779; PMCID: PMC2824149. [PMC free article: PMC2824149] [PubMed: 19966779]
31. Cossette P, Lachance-Touchette P, Rouleau GA. Mutated GABA_A  receptor subunits in idiopathic generalized epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 714–730. [PubMed: 22787675]
32. Crawshaw AA, Cock HR.  Medical management of status epilepticus: Emergency room to intensive care unit.  Seizure. 2020 Feb;75:145–152. doi: 10.1016/j.seizure.2019.10.006. Epub 2019 Oct 24. PMID: 31722820. [PubMed: 31722820]
33. Crestani F, Assandri R, Täuber M, Martin JR, Rudolph U. Contribution of the α1-GABA_A receptor subtype to the pharmacological actions of benzodiazepine site inverse agonists. Neuropharmacology. 2002 Sep;43(4):679–84. doi: 10.1016/s0028-3908(02)00159-4. PMID: 12367613. [PubMed: 12367613]
34. Crunelli V, Lersche N, Cope DW. GABA_A  receptor function in typical absence seizures. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 228–241.
35. Davenport EC, Pendolino V, Kontou G, McGee TP, Sheehan DF, López-Doménech G, Farrant M, Kittler JT. An essential role for the tetraspanin LHFPL4 in the cell-type-specific targeting and clustering of synaptic GABA_A receptors. Cell Rep. 2017 Oct 3;21(1):70–83. doi: 10.1016/j.celrep.2017.09.025. PMID: 28978485; PMCID: PMC5640807. [PMC free article: PMC5640807] [PubMed: 28978485]
36. Dejanovic B, Djémié T, Grünewald N, Suls A, Kress V, Hetsch F, Craiu D, Zemel M, Gormley P, Lal D; EuroEPINOMICS Dravet working group, Myers CT, Mefford HC, Palotie A, Helbig I, Meier JC, De Jonghe P, Weckhuysen S, Schwarz G.  Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy.  EMBO Mol Med. 2015 Dec;7(12):1580–94. doi: 10.15252/emmm.201505323. PMID: 26613940; PMCID: PMC4693503. [PMC free article: PMC4693503] [PubMed: 26613940]
37. Drasbek KR, Jensen K. THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABA_A receptor- mediated conductance in mouse neocortex. Cereb Cortex. 2006 Aug;16(8):1134–41. doi: 10.1093/cercor/bhj055. Epub 2005 Oct 12. PMID: 16221925. [PubMed: 16221925]
38. Duveau V, Buhl DL, Evrard A, Ruggiero C, Mandé-Niedergang B, Roucard C, Gurrell R. Pronounced antiepileptic activity of the subtype-selective GABA_A -positive allosteric modulator PF-06372865 in the GAERS absence epilepsy model. CNS Neurosci Ther. 2019 Feb;25(2):255–260. doi: 10.1111/cns.13046. Epub 2018 Aug 12. PMID: 30101518; PMCID: PMC6488884. [PMC free article: PMC6488884] [PubMed: 30101518]
39. Eadie MJ.  William Gowers’ interpretation of epileptogenic mechanisms: 1880-1906.  Epilepsia. 2011 Jun;52(6):1045–51. doi: 10.1111/j.1528-1167.2011.02983.x. Epub 2011 Mar 22. PMID: 21434889. [PubMed: 21434889]
40. Eaton MM, Germann AL, Arora R, Cao LQ, Gao X, Shin DJ, Wu A, Chiara DC, Cohen JB, Steinbach JH, Evers AS, Akk G. Multiple non-equivalent interfaces mediate direct activation of GABA_A receptors by propofol. Curr Neuropharmacol.  2016;14(7):772–80. doi: 10.2174/1570159x14666160202121319. PMID: 26830963; PMCID: PMC5050400. [PMC free article: PMC5050400] [PubMed: 26830963]
41. Engin E, Benham RS, Rudolph U. An emerging circuit pharmacology of GABA_A receptors. Trends Pharmacol Sci. 2018 Aug;39(8):710–732. doi: 10.1016/j.tips.2018.04.003. Epub 2018 Jun 11. PMID: 29903580; PMCID: PMC6056379. [PMC free article: PMC6056379] [PubMed: 29903580]
42. Fariello RG, Golden GT.  The THIP-induced model of bilateral synchronous spike and wave in rodents.  Neuropharmacology. 1987 Feb-Mar;26(2-3):161–5. doi: 10.1016/0028-3908(87)90204-8. PMID: 3587530. [PubMed: 3587530]
43. Farrar SJ, Whiting PJ, Bonnert TP, McKernan RM.  Stoichiometry of a ligand-gated ion channel determined by fluorescence energy transfer.  J Biol Chem. 1999 Apr 9;274(15):10100–4. doi: 10.1074/jbc.274.15.10100. PMID: 10187791. [PubMed: 10187791]
44. Ferando I, Mody I. Interneuronal GABA_A receptors inside and outside of synapses. Curr Opin Neurobiol. 2014 Jun;26:57–63. doi: 10.1016/j.conb.2013.12.001. Epub 2013 Dec 29. PMID: 24650505; PMCID: PMC4024329. [PMC free article: PMC4024329] [PubMed: 24650505]
45. ffrench-Mullen JM, Barker JL, Rogawski MA.  Calcium current block by (-)-pentobarbital, phenobarbital, and CHEB but not (+)-pentobarbital in acutely isolated hippocampal CA1 neurons: comparison with effects on GABA-activated Cl- current.  J Neurosci. 1993 Aug;13(8):3211–21. doi: 10.1523/JNEUROSCI.13-08-03211.1993. PMID: 8101867; PMCID: PMC6576525. [PMC free article: PMC6576525] [PubMed: 8101867]
46. Field M, Lukacs IP, Hunter E, Stacey R, Plaha P, Livermore L, Ansorge O, Somogyi P. Tonic GABA_A receptor-mediated currents of human cortical GABAergic interneurons vary amongst cell types. J Neurosci. 2021 Nov 24;41(47):9702–9719. doi: 10.1523/JNEUROSCI.0175-21.2021. Epub 2021 Oct 19. PMID: 34667071; PMCID: PMC8612645. [PMC free article: PMC8612645] [PubMed: 34667071]
47. Fischell J, Van Dyke AM, Kvarta MD, LeGates TA, Thompson SM. Rapid antidepressant action and restoration of excitatory synaptic strength after chronic stress by negative modulators of alpha5-containing GABA_A receptors. Neuropsychopharmacology. 2015 Oct;40(11):2499–509. doi: 10.1038/npp.2015.112. Epub 2015 Apr 22. PMID: 25900119; PMCID: PMC4569955. [PMC free article: PMC4569955] [PubMed: 25900119]
48. Fisher JL. The anti-convulsant stiripentol acts directly on the GABA_A receptor as a positive allosteric modulator. Neuropharmacology. 2009 Jan;56(1):190–7. doi: 10.1016/j.neuropharm.2008.06.004. Epub 2008 Jun 10. PMID: 18585399; PMCID: PMC2665930. [PMC free article: PMC2665930] [PubMed: 18585399]
49. Förstera B, Belaidi AA, Jüttner R, Bernert C, Tsokos M, Lehmann TN, Horn P, Dehnicke C, Schwarz G, Meier JC. Irregular RNA splicing curtails postsynaptic gephyrin in the cornu ammonis of patients with epilepsy. Brain. 2010 Dec;133(Pt 12):3778–94. doi: 10.1093/brain/awq298. Epub 2010 Nov 10. PMID: 21071388. [PubMed: 21071388]
50. Fradley RL, Guscott MR, Bull S, Hallett DJ, Goodacre SC, Wafford KA, Garrett EM, Newman RJ, O’Meara GF, Whiting PJ, Rosahl TW, Dawson GR, Reynolds DS, Atack JR. Differential contribution of GABA_A receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands. J Psychopharmacol. 2007 Jun;21(4):384–91. doi: 10.1177/0269881106067255. Epub 2006 Nov 8. PMID: 17092983. [PubMed: 17092983]
51. Fritschy J-M, Panzanelli P, Tyagarajan SK.  Molecular and functional heterogeneity of GABAergic synapses.  Cell Mol Life Sci. 2012 Aug;69(15):2485–99. doi: 10.1007/s00018-012-0926-4. PMID: 22314501. [PMC free article: PMC11115047] [PubMed: 22314501]
52. Fritschy J-M. Epilepsy, E/I balance and GABA_A receptor plasticity. Front Mol Neurosci. 2008 Mar 28;1:5. doi: 10.3389/neuro.02.005.2008. PMID: 18946538; PMCID: PMC2525999. [PMC free article: PMC2525999] [PubMed: 18946538]
53. Germann AL, Pierce SR, Tateiwa H, Sugasawa Y, Reichert DE, Evers AS, Steinbach JH, Akk G. Intrasubunit and intersubunit steroid binding sites independently and additively mediate α1β2γ2L GABA_A receptor potentiation by the endogenous neurosteroid allopregnanolone. Mol Pharmacol. 2021 Jul;100(1):19–31. doi: 10.1124/molpharm.121.000268. Epub 2021 May 6. PMID: 33958479; PMCID: PMC8256884. [PMC free article: PMC8256884] [PubMed: 33958479]
54. Glykys J, Mann EO, Mody I. Which GABA_A receptor subunits are necessary for tonic inhibition in the hippocampus? J Neurosci.  2008 Feb 6;28(6):1421–6. doi: 10.1523/JNEUROSCI.4751-07.2008. PMID: 18256262; PMCID: PMC6671570. [PMC free article: PMC6671570] [PubMed: 18256262]
55. Grasshoff C, Drexler B, Rudolph U, Antkowiak B.  Anaesthetic drugs: linking molecular actions to clinical effects.  Curr Pharm Des.  2006;12(28):3665–79. doi: 10.2174/138161206778522038. PMID: 17073666. [PubMed: 17073666]
56. Grasshoff C, Jurd R, Rudolph U, Antkowiak B. Modulation of presynaptic β3-containing GABA_A receptors limits the immobilizing actions of GABAergic anesthetics. Mol Pharmacol. 2007 Sep;72(3):780–7. doi: 10.1124/mol.107.037648. Epub 2007 Jun 21. PMID: 17584992. [PubMed: 17584992]
57. Gravielle MC. Activation-induced regulation of GABAA receptors: Is there a link with the molecular basis of benzodiazepine tolerance?  Pharmacol Res. 2016 Jul;109:92-100. doi: 10.1016/j.phrs.2015.12.030. Epub 2015 Dec 28. PMID: 26733466. [PubMed: 26733466]
58. Gurrell R, Gorman D, Whitlock M, Ogden A, Reynolds DS, DiVentura B, Abou-Khalil B, Gelfand M, Pollard J, Hogan RE, Krauss G, Sperling M, Vazquez B, Wechsler RT, Friedman D, Butt RP, French J.  Photosensitive epilepsy: Robust clinical efficacy of a selective GABA potentiator.  Neurology. 2019 Apr 9;92(15):e1786–e1795. doi: 10.1212/WNL.0000000000007271. Epub 2019 Mar 15. PMID: 30877186. [PubMed: 30877186]
59. Haigh JR, Pullar T, Gent JP, Dailley C, Feely M. N- desmethylclobazam: a possible alternative to clobazam in the treatment of refractory epilepsy? Br J Clin Pharmacol. 1987 Feb;23(2):213–8. doi: 10.1111/j.1365-2125.1987.tb03032.x. PMID: 3828198; PMCID: PMC1386071. [PMC free article: PMC1386071] [PubMed: 3828198]
60. Hales TG, Lambert JJ.  The actions of propofol on inhibitory amino acid receptors of bovine adrenomedullary chromaffin cells and rodent central neurones.  Br J Pharmacol. 1991 Nov;104(3):619–28. doi: 10.1111/j.1476-5381.1991.tb12479.x. PMID: 1665745; PMCID: PMC1908220. [PMC free article: PMC1908220] [PubMed: 1665745]
61. Hammer H, Ebert B, Jensen HS, Jensen AA. Functional characterization of the 1,5-benzodiazepine clobazam and its major active metabolite N-desmethylclobazam at human GABA_A receptors expressed in Xenopus laevis oocytes. PLoS One. 2015 Mar 23;10(3):e0120239. doi: 10.1371/journal.pone.0120239. PMID: 25798598; PMCID: PMC4370687. [PMC free article: PMC4370687] [PubMed: 25798598]
62. Han S, Tai C, Westenbroek RE, Yu FH, Cheah CS, Potter GB, Rubenstein JL, Scheuer T, de la Iglesia HO, Catterall WA. Autistic-like behaviour in Scn1a^+/- mice and rescue by enhanced GABA-mediated neurotransmission. Nature. 2012 Sep 20;489(7416):385–90. doi: 10.1038/nature11356. Epub 2012 Aug 22. PMID: 22914087; PMCID: PMC3448848. [PMC free article: PMC3448848] [PubMed: 22914087]
63. Hanchar HJ, Dodson PD, Olsen RW, Otis TS, Wallner M. Alcohol-induced motor impairment caused by increased extrasynaptic GABA_A receptor activity. Nat Neurosci. 2005 Mar;8(3):339–45. doi: 10.1038/nn1398. Epub 2005 Feb 6. PMID: 15696164; PMCID: PMC2854077. [PMC free article: PMC2854077] [PubMed: 15696164]
64. Hernandez CC, XiangWei W, Hu N, Shen D, Shen W, Lagrange AH, Zhang Y, Dai L, Ding C, Sun Z, Hu J, Zhu H, Jiang Y, Macdonald RL.  Altered inhibitory synapses in de novo GABRA5 and GABRA1 mutations associated with early onset epileptic encephalopathies.  Brain. 2019 Jul 1;142(7):1938–1954. doi: 10.1093/brain/awz123. PMID: 31056671; PMCID: PMC6598634. [PMC free article: PMC6598634] [PubMed: 31056671]
65. Hernandez CC, Zhang Y, Hu N, Shen D, Shen W, Liu X, Kong W, Jiang Y, Macdonald RL. GABA_A receptor coupling junction and pore GABRB3 mutations are linked to early-onset epileptic encephalopathy. Sci Rep. 2017 Nov 21;7(1):15903. doi: 10.1038/s41598-017-16010-3. PMID: 29162865; PMCID: PMC5698489. [PMC free article: PMC5698489] [PubMed: 29162865]
66. Hernandez TD, Heninger C, Wilson MA, Gallager DW.  Relationship of agonist efficacy to changes in GABA sensitivity and anticonvulsant tolerance following chronic benzodiazepine ligand exposure.  Eur J Pharmacol. 1989 Nov 7;170(3):145–55. doi: 10.1016/0014-2999(89)90535-9. PMID: 2515976. [PubMed: 2515976]
67. Hille B, Dickson EJ, Kruse M, Vivas O, Suh BC.  Phosphoinositides regulate ion channels.  Biochim Biophys Acta. 2015 Jun;1851(6):844–56. doi: 10.1016/j.bbalip.2014.09.010. Epub 2014 Sep 18. PMID: 25241941; PMCID: PMC4364932. [PMC free article: PMC4364932] [PubMed: 25241941]
68. Hines RM, Maric HM, Hines DJ, Modgil A, Panzanelli P, Nakamura Y, Nathanson AJ, Cross A, Deeb T, Brandon NJ, Davies P, Fritschy JM, Schindelin H, Moss SJ. Developmental seizures and mortality result from reducing GABA_A receptor α2-subunit interaction with collybistin. Nat Commun. 2018 Aug 7;9(1):3130. doi: 10.1038/s41467-018-05481-1. PMID: 30087324; PMCID: PMC6081406. [PMC free article: PMC6081406] [PubMed: 30087324]
69. Hosie AM, Clarke L, da Silva H, Smart TG.  Conserved site for neurosteroid modulation of GABA A receptors.  Neuropharmacology. 2009 Jan;56(1):149–54. doi: 10.1016/j.neuropharm.2008.07.050. Epub 2008 Aug 13. PMID: 18762201. [PubMed: 18762201]
70. Hosie AM, Wilkins ME, da Silva HM, Smart TG. Endogenous neurosteroids regulate GABA_A receptors through two discrete transmembrane sites. Nature. 2006 Nov 23;444(7118):486–9. doi: 10.1038/nature05324. Epub 2006 Nov 15. PMID: 17108970. [PubMed: 17108970]
71. Houser CR, Zhang N, Peng Z. Alterations in the distribution of GABA_A  receptors in epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 532–544.
72. Houser CR. Do structural changes in GABA neurons give rise to the epileptic state? Adv Exp Med Biol. 2014;813:151–60. doi: 10.1007/978-94-017-8914-1_12. PMID: 25012374; PMCID: PMC4634888. [PMC free article: PMC4634888] [PubMed: 25012374]
73. Jacob TC. Neurobiology and therapeutic potential of α5-GABA type A receptors. Front Mol Neurosci. 2019 Jul 24;12:179. doi: 10.3389/fnmol.2019.00179. PMID: 31396049; PMCID: PMC6668551. [PMC free article: PMC6668551] [PubMed: 31396049]
74. Janković SM, Dješević M, Janković SV.  Experimental GABA A Receptor Agonists and Allosteric Modulators for the Treatment of Focal Epilepsy.  J Exp Pharmacol.  2021 Mar 8;13:235–244. doi: 10.2147/JEP.S242964. PMID: 33727865; PMCID: PMC7954424. [PMC free article: PMC7954424] [PubMed: 33727865]
75. Jayakar SS, Zhou X, Chiara DC, Jarava-Barrera C, Savechenkov PY, Bruzik KS, Tortosa M, Miller KW, Cohen JB. Identifying drugs that bind selectively to intersubunit general anesthetic sites in the α1β3γ2 GABA_A R transmembrane domain. Mol Pharmacol. 2019 Jun;95(6):615–628. doi: 10.1124/mol.118.114975. Epub 2019 Apr 5. PMID: 30952799; PMCID: PMC6505378. [PMC free article: PMC6505378] [PubMed: 30952799]
76. Johannesen K, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad CE, Gardella E, Weber Y, Søndergård M, Hjalgrim H, Nikanorova M, Becker F, Larsen LH, Dahl HA, Maier O, Mei D, Biskup S, Klein KM, Reif PS, Rosenow F, Elias AF, Hudson C, Helbig KL, Schubert-Bast S, Scordo MR, Craiu D, Djémié T, Hoffman-Zacharska D, Caglayan H, Helbig I, Serratosa J, Striano P, De Jonghe P, Weckhuysen S, Suls A, Muru K, Talvik I, Talvik T, Muhle H, Borggraefe I, Rost I, Guerrini R, Lerche H, Lemke JR, Rubboli G, Maljevic S. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies. Neurology. 2016 Sep 13;87(11):1140–51. doi: 10.1212/WNL.0000000000003087. Epub 2016 Aug 12. PMID: 27521439. [PubMed: 27521439]
77. Joshi S, Kapur J. GABA_A  receptor plasticity during status epilepticus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 545–554.
78. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U. General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA_A receptor β3 subunit. FASEB J. 2003 Feb;17(2):250–2. doi: 10.1096/fj.02-0611fje. Epub 2002 Dec 3. PMID: 12475885. [PubMed: 12475885]
79. Kadriu B, Guidotti A, Costa E, Auta J.  Imidazenil, a non-sedating anticonvulsant benzodiazepine, is more potent than diazepam in protecting against DFP-induced seizures and neuronal damage.  Toxicology. 2009 Feb 27;256(3):164–74. doi: 10.1016/j.tox.2008.11.021. Epub 2008 Dec 7. PMID: 19111886. [PubMed: 19111886]
80. Kang JQ, Macdonald RL. Molecular pathogenic basis for GABRG2 mutations associated with a spectrum of epilepsy syndromes, from generalized absence epilepsy to Dravet syndrome. JAMA Neurol. 2016 Aug 1;73(8):1009–16. doi: 10.1001/jamaneurol.2016.0449. PMID: 27367160; PMCID: PMC5426359. [PMC free article: PMC5426359] [PubMed: 27367160]
81. Kang M, Spigelman I, Sapp DW, Olsen RW. Persistent reduction of GABA_A receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment. Brain Res. 1996 Feb 19;709(2):221–8. doi: 10.1016/0006-8993(95)01274-5. PMID: 8833758. [PubMed: 8833758]
82. Kasugai Y, Swinny JD, Roberts JD, Dalezios Y, Fukazawa Y, Sieghart W, Shigemoto R, Somogyi P. Quantitative localisation of synaptic and extrasynaptic GABA_A receptor subunits on hippocampal pyramidal cells by freeze-fracture replica immunolabelling. Eur J Neurosci. 2010 Dec;32(11):1868–88. doi: 10.1111/j.1460-9568.2010.07473.x. Epub 2010 Nov 14. PMID: 21073549; PMCID: PMC4487817. [PMC free article: PMC4487817] [PubMed: 21073549]
83. Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE.  Shared structural mechanisms of general anaesthetics and benzodiazepines.  Nature. 2020 Sep;585(7824):303–308. doi: 10.1038/s41586-020-2654-5. Epub 2020 Sep 2. PMID: 32879488; PMCID: PMC7486282. [PMC free article: PMC7486282] [PubMed: 32879488]
84. Kim S, Kang M, Park D, Lee AR, Betz H, Ko J, Chang I, Um JW.  Impaired formation of high-order gephyrin oligomers underlies gephyrin dysfunction-associated pathologies.  iScience. 2021 Jan 7;24(2):102037. doi: 10.1016/j.isci.2021.102037. PMID: 33532714; PMCID: PMC7822942. [PMC free article: PMC7822942] [PubMed: 33532714]
85. Kinoshita M, Ikeda A, Begum T, Terada K, Shibasaki H.  Efficacy of low-dose, add-on therapy of clobazam (CLB) is produced by its major metabolite, N- desmethyl-CLB.  J Neurol Sci. 2007 Dec 15;263(1–2):44–8. doi: 10.1016/j.jns.2007.05.025. Epub 2007 Jun 22. PMID: 17588610. [PubMed: 17588610]
86. Kleingoor C, Ewert M, von Blankenfeld G, Seeburg PH, Kettenmann H. Inverse but not full benzodiazepine agonists modulate recombinant alpha α6β2γ2 GABA_A receptors in transfected human embryonic kidney cells. Neurosci Lett. 1991 Sep 16;130(2):169–72. doi: 10.1016/0304-3940(91)90389-b. PMID: 1665550. [PubMed: 1665550]
87. Knutson DE, Smith JL, Ping X, Jin X, Golani LK, Li G, Tiruveedhula VVNPB, Rashid F, Mian MY, Jahan R, Sharmin D, Cerne R, Cook JM, Witkin JM. Imidazodiazepine anticonvulsant, KRM-II-81, produces novel, non-diazepam-like antiseizure effects. ACS Chem Neurosci. 2020 Sep 2;11(17):2624–2637. doi: 10.1021/acschemneuro.0c00295. Epub 2020 Aug 18. PMID: 32786313. [PubMed: 32786313]
88. Kumar SS, Buckmaster PS.  Hyperexcitability, interneurons, and loss of GABAergic synapses in entorhinal cortex in a model of temporal lobe epilepsy.  J Neurosci. 2006 Apr 26;26(17):4613–23. doi: 10.1523/JNEUROSCI.0064-06.2006. PMID: 16641241; PMCID: PMC6674073. [PMC free article: PMC6674073] [PubMed: 16641241]
89. Lachance-Touchette P, Brown P, Meloche C, Kinirons P, Lapointe L, Lacasse H, Lortie A, Carmant L, Bedford F, Bowie D, Cossette P. Novel α1 and γ2 GABA_A receptor subunit mutations in families with idiopathic generalized epilepsy. Eur J Neurosci. 2011 Jul;34(2):237–49. doi: 10.1111/j.1460-9568.2011.07767.x. Epub 2011 Jun 30. PMID: 21714819. [PubMed: 21714819]
90. Laverty D, Desai R, Uchański T, Masiulis S, Stec WJ, Malinauskas T, Zivanov J, Pardon E, Steyaert J, Miller KW, Aricescu AR. Cryo-EM structure of the human α1β3γ2 GABA_A receptor in a lipid bilayer. Nature. 2019 Jan;565(7740):516–520. doi: 10.1038/s41586-018-0833-4. Epub 2019 Jan 2. PMID: 30602789; PMCID: PMC6364807. [PMC free article: PMC6364807] [PubMed: 30602789]
91. Laverty D, Thomas P, Field M, Andersen OJ, Gold MG, Biggin PC, Gielen M, Smart TG. Crystal structures of a GABA_A -receptor chimera reveal new endogenous neurosteroid-binding sites. Nat Struct Mol Biol. 2017 Nov;24(11):977–985. doi: 10.1038/nsmb.3477. Epub 2017 Oct 2. PMID: 28967882; PMCID: PMC6853794. [PMC free article: PMC6853794] [PubMed: 28967882]
92. Lee V, Maguire J. The impact of tonic GABA_A receptor-mediated inhibition on neuronal excitability varies across brain region and cell type. Front Neural Circuits. 2014 Feb 3;8:3. doi: 10.3389/fncir.2014.00003. PMID: 24550784; PMCID: PMC3909947. [PMC free article: PMC3909947] [PubMed: 24550784]
93. Legesse DH, Fan C, Teng J, Zhuang Y, Howard RJ, Noviello CM, Lindahl E, Hibbs RE. Structural insights into opposing actions of neurosteroids on GABAA receptors.  Nat Commun. 2023 Aug 22;14(1):5091. doi: 10.1038/s41467-023-40800-1. PMID: 37607940; PMCID: PMC10444788. [PMC free article: PMC10444788] [PubMed: 37607940]
94. Li G-D, Chiara DC, Cohen JB, Olsen RW. Neurosteroids allosterically modulate binding of the anesthetic etomidate to γ-aminobutyric acid type A receptors. J Biol Chem. 2009 May 1;284(18):11771–5. doi: 10.1074/jbc.C900016200. Epub 2009 Mar 12. PMID: 19282280; PMCID: PMC2673245. [PMC free article: PMC2673245] [PubMed: 19282280]
95. Lin W-C, Tsai MC, Davenport CM, Smith CM, Veit J, Wilson NM, Adesnik H, Kramer RH. A comprehensive optogenetic pharmacology toolkit for in vivo control of GABA_A receptors and synaptic inhibition. Neuron. 2015 Dec 2;88(5):879–891. doi: 10.1016/j.neuron.2015.10.026. Epub 2015 Nov 19. PMID: 26606997; PMCID: PMC4775236. [PMC free article: PMC4775236] [PubMed: 26606997]
96. Liang J, Cagetti E, Olsen RW, Spigelman I. Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence.  J Pharmacol Exp Ther. 2004 Sep;310(3):1234–45. doi: 10.1124/jpet.104.067983. Epub 2004 May 4. PMID: 15126642. [PubMed: 15126642]
97. Lindemeyer AK, Liang J, Marty VN, Meyer EM, Suryanarayanan A, Olsen RW, Spigelman I. Ethanol-induced plasticity of GABA_A receptors in the basolateral amygdala. Neurochem Res. 2014 Jun;39(6):1162–70. doi: 10.1007/s11064-014-1297-z. Epub 2014 Apr 8. PMID: 24710789; PMCID: PMC4121120. [PMC free article: PMC4121120] [PubMed: 24710789]
98. Lindemeyer AK, Shen Y, Yazdani F, Shao XM, Spigelman I, Davies DL, Olsen RW, Liang J. α2 subunit- containing GABA_A receptor subtypes are upregulated and contribute to alcohol-induced functional plasticity in the rat hippocampus. Mol Pharmacol. 2017 Aug;92(2):101–112. doi: 10.1124/mol.116.107797. Epub 2017 May 23. PMID: 28536106; PMCID: PMC5508196. [PMC free article: PMC5508196] [PubMed: 28536106]
99. Lionel AC, Vaags AK, Sato D, Gazzellone MJ, Mitchell EB, Chen HY, Costain G, Walker S, Egger G, Thiruvahindrapuram B, Merico D, Prasad A, Anagnostou E, Fombonne E, Zwaigenbaum L, Roberts W, Szatmari P, Fernandez BA, Georgieva L, Brzustowicz LM, Roetzer K, Kaschnitz W, Vincent JB, Windpassinger C, Marshall CR, Trifiletti RR, Kirmani S, Kirov G, Petek E, Hodge JC, Bassett AS, Scherer SW.  Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures.  Hum Mol Genet. 2013 May 15;22(10):2055–66. doi: 10.1093/hmg/ddt056. Epub 2013 Feb 7. PMID: 23393157. [PubMed: 23393157]
100. Löscher W, Rogawski MA.  How theories evolved concerning the mechanism of action of barbiturates.  Epilepsia. 2012 Dec;53 Suppl 8:12–25. doi: 10.1111/epi.12025. PMID: 23205959. [PubMed: 23205959]
101. Löscher W, Schwark WS.  Evaluation of different GABA receptor agonists in the kindled amygdala seizure model in rats.  Exp Neurol. 1985 Aug;89(2):454–60. doi: 10.1016/0014-4886(85)90104-9. PMID: 2990987. [PubMed: 2990987]
102. Loup F, Wieser HG, Yonekawa Y, Aguzzi A, Fritschy JM. Selective alterations in GABA_A receptor subtypes in human temporal lobe epilepsy. J Neurosci.  2000a Jul 15;20(14):5401–19. doi: 10.1523/JNEUROSCI.20-14-05401.2000. PMID: 10884325; PMCID: PMC6772330. [PMC free article: PMC6772330] [PubMed: 10884325]
103. Löw K, Crestani F, Keist R, Benke D, Brünig I, Benson JA, Fritschy JM, Rülicke T, Bluethmann H, Möhler H, Rudolph U.  Molecular and neuronal substrate for the selective attenuation of anxiety.  Science. 2000 Oct 6;290(5489):131–4. doi: 10.1126/science.290.5489.131. PMID: 11021797. [PubMed: 11021797]
104. Macdonald RL, Kang J-Q, Gallagher MJ. GABA_A  receptor subunit mutations and genetic epilepsies. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 740–749.
105. Mäkelä R, Uusi-Oukari M, Homanics GE, Quinlan JJ, Firestone LL, Wisden W, Korpi ER. Cerebellar γ- aminobutyric acid type A receptors: pharmacological subtypes revealed by mutant mouse lines. Mol Pharmacol. 1997 Sep;52(3):380–8. doi: 10.1124/mol.52.3.380. PMID: 9281599. [PubMed: 9281599]
106. Maljevic S, Møller RS, Reid CA, Pérez-Palma E, Lal D, May P, Lerche H. Spectrum of GABA_A receptor variants in epilepsy. Curr Opin Neurol. 2019 Apr;32(2):183–190. doi: 10.1097/WCO.0000000000000657. PMID: 30664068. [PubMed: 30664068]
107. Markram H, Toledo-Rodriguez M, Wang Y, Gupta A, Silberberg G, Wu C.  Interneurons of the neocortical inhibitory system.  Nat Rev Neurosci. 2004 Oct;5(10):793–807. doi: 10.1038/nrn1519. PMID: 15378039. [PubMed: 15378039]
108. Martin LJ, Zurek AA, MacDonald JF, Roder JC, Jackson MF, Orser BA.  α5 GABA_A receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory. J Neurosci. 2010 Apr 14;30(15):5269–82. doi: 10.1523/JNEUROSCI.4209-09.2010. PMID: 20392949; PMCID: PMC6632746. [PMC free article: PMC6632746] [PubMed: 20392949]
109. Masiulis S, Desai R, Uchański T, Serna Martin I, Laverty D, Karia D, Malinauskas T, Zivanov J, Pardon E, Kotecha A, Steyaert J, Miller KW, Aricescu AR. GABA_A receptor signalling mechanisms revealed by structural pharmacology. Nature. 2019 Jan;565(7740):454–459. doi: 10.1038/s41586–018-0832–5. PMID: 30602790; PMCID: PMC6370056 [PMC free article: PMC6370056] [PubMed: 30602790]
110. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ. Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA_A receptor α1 subtype. Nat Neurosci. 2000 Jun;3(6):587–92. doi: 10.1038/75761. PMID: 10816315. [PubMed: 10816315]
111. Meera P, Wallner M, Otis TS. Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA_A receptors. J Neurophysiol. 2011 Oct;106(4):2057–64. doi: 10.1152/jn.00450.2011. Epub 2011 Jul 27. PMID: 21795619; PMCID: PMC3191842. [PMC free article: PMC3191842] [PubMed: 21795619]
112. Megarbane B, Lesguillons N, Galliot-Guilley M, Borron SW, Trout H, Declèves X, Risède P, Monier C, Boschi G, Baud FJ.  Cerebral and plasma kinetics of a high dose of midazolam and correlations with its respiratory effects in rats.  Toxicol Lett. 2005 Oct 15;159(1):22–31. doi: 10.1016/j.toxlet.2005.04.003. PMID: 15916873. [PubMed: 15916873]
113. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z, DeLorey TM, Olsen RW, Homanics GE. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12905–10. doi: 10.1073/pnas.96.22.12905. PMID: 10536021; PMCID: PMC23157. [PMC free article: PMC23157] [PubMed: 10536021]
114. Miller PS, Scott S, Masiulis S, De Colibus L, Pardon E, Steyaert J, Aricescu AR. Structural basis for GABA_A receptor potentiation by neurosteroids. Nat Struct Mol Biol. 2017 Nov;24(11):986–992. doi: 10.1038/nsmb.3484. Epub 2017 Oct 9. PMID: 28991263; PMCID: PMC6166781. [PMC free article: PMC6166781] [PubMed: 28991263]
115. Mody I. Plasticity of GABA_A  receptors relevant to neurosteroid actions. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 555–561.
116. Möhler H. GABA_A receptors in central nervous system disease: anxiety, epilepsy, and insomnia. J Recept Signal Transduct Res.  2006;26(5–6):731–40. doi: 10.1080/10799890600920035. PMID: 17118808. [PubMed: 17118808]
117. Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, Vaher U, Borggraefe I, Talvik I, Talvik T, Kluger G, Francois LL, Lesca G, de Bellescize J, Blichfeldt S, Chatron N, Holert N, Jacobs J, Swinkels M, Betzler C, Syrbe S, Nikanorova M, Myers CT, Larsen LH, Vejzovic S, Pendziwiat M, von Spiczak S, Hopkins S, Dubbs H, Mang Y, Mukhin K, Holthausen H, van Gassen KL, Dahl HA, Tommerup N, Mefford HC, Rubboli G, Guerrini R, Lemke JR, Lerche H, Muhle H, Maljevic S. Mutations in GABRB3: From febrile seizures to epileptic encephalopathies. Neurology. 2017 Jan 31;88(5):483–492. doi: 10.1212/WNL.0000000000003565. Epub 2017 Jan 4. PMID: 28053010; PMCID: PMC5278942. [PMC free article: PMC5278942] [PubMed: 28053010]
118. Mortensen M, Patel B, Smart TG.  GABA potency at GABAA receptors found in synaptic and extrasynaptic zones.  Front Cell Neurosci. 2012 Jan 20;6:1. doi: 10.3389/fncel.2012.00001. PMID: 22319471; PMCID: PMC3262152. [PMC free article: PMC3262152] [PubMed: 22319471]
119. Nathanson AJ, Zhang Y, Smalley JL, Ollerhead TA, Rodriguez Santos MA, Andrews PM, Wobst HJ, Moore YE, Brandon NJ, Hines RM, Davies PA, Moss SJ. Identification of a core amino acid motif within the α subunit of GABA_A Rs that promotes inhibitory synaptogenesis and resilience to seizures. Cell Rep. 2019 Jul 16;28(3):670–681.e8. doi: 10.1016/j.celrep.2019.06.014. PMID: 31315046; PMCID: PMC8283774. [PMC free article: PMC8283774] [PubMed: 31315046]
120. Natolino F, Zanotti A, Contarino A, Lipartiti M, Giusti P.  Abecarnil, a beta-carboline derivative, does not exhibit anticonvulsant tolerance or withdrawal effects in mice.  Naunyn Schmiedebergs Arch Pharmacol.  1996 Nov;354(5):612–7. doi: 10.1007/BF00170836. PMID: 8938660. [PubMed: 8938660]
121. Nickolls SA, Gurrell R, van Amerongen G, Kammonen J, Cao L, Brown AR, Stead C, Mead A, Watson C, Hsu C, Owen RM, Pike A, Fish RL, Chen L, Qiu R, Morris ED, Feng G, Whitlock M, Gorman D, van Gerven J, Reynolds DS, Dua P, Butt RP. Pharmacology in translation: the preclinical and early clinical profile of the novel α2/3 functionally selective GABA_A receptor positive allosteric modulator PF-06372865. Br J Pharmacol. 2018 Feb;175(4):708–725. doi: 10.1111/bph.14119. PMID: 29214652; PMCID: PMC5786456. [PMC free article: PMC5786456] [PubMed: 29214652]
122. Nusser Z, Sieghart W, Benke D, Fritschy J-M, Somogyi P. Differential synaptic localization of two major γ- aminobutyric acid type A receptor α subunits on hippocampal pyramidal cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11939–44. doi: 10.1073/pnas.93.21.11939. PMID: 8876241; PMCID: PMC38162. [PMC free article: PMC38162] [PubMed: 8876241]
123. Nyíri G, Freund TF, Somogyi P. Input-dependent synaptic targeting of α₂-subunit-containing GABA_A receptors in synapses of hippocampal pyramidal cells of the rat. Eur J Neurosci. 2001 Feb;13(3):428–42. doi: 10.1046/j.1460-9568.2001.01407.x. PMID: 11168550. [PubMed: 11168550]
124. Ohsumi Y.  Molecular dissection of autophagy: two ubiquitin-like systems.  Nat Rev Mol Cell Biol. 2001 Mar;2(3):211–6. doi: 10.1038/35056522. PMID: 11265251. [PubMed: 11265251]
125. Olsen RW. GABA_A receptor: Positive and negative allosteric modulators. Neuropharmacology. 2018 Jul 1;136(Pt A):10–22. doi: 10.1016/j.neuropharm.2018.01.036. Epub 2018 Jan 31. PMID: 29407219; PMCID: PMC6027637. [PMC free article: PMC6027637] [PubMed: 29407219]
126. Olsen RW, Hanchar HJ, Meera P, Wallner M. GABA_A receptor subtypes: the “one glass of wine” receptors. Alcohol. 2007 May;41(3):201–9. doi: 10.1016/j.alcohol.2007.04.006. PMID: 17591543; PMCID: PMC2852584. [PMC free article: PMC2852584] [PubMed: 17591543]
127. Olsen RW, Liang J. Role of GABA_A receptors in alcohol use disorders suggested by chronic intermittent ethanol (CIE) rodent model. Mol Brain. 2017 Sep 20;10(1):45. doi: 10.1186/s13041-017-0325-8. PMID: 28931433; PMCID: PMC5605989. [PMC free article: PMC5605989] [PubMed: 28931433]
128. Olsen RW, Lindemeyer AK, Wallner M, Li X, Huynh KW, Zhou ZH. Cryo-electron microscopy reveals informative details of GABA_A receptor structural pharmacology: implications for drug discovery. Ann Transl Med. 2019 Jul;7(Suppl 3):S144. doi: 10.21037/atm.2019.06.23. PMID: 31576351; PMCID: PMC6685854. [PMC free article: PMC6685854] [PubMed: 31576351]
129. Olsen RW, Sieghart W. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit composition, pharmacology, and function. Update.  Pharmacol Rev. 2008 Sep;60(3):243–60. doi: 10.1124/pr.108.00505. Epub 2008 Sep 12. PMID: 18790874; PMCID: PMC2847512. [PMC free article: PMC2847512] [PubMed: 18790874]
130. Olsen RW, Spigelman I. GABA_A  receptor plasticity in alcohol withdrawal. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 562–573.
131. Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA.  Ion channels in genetic epilepsy: From genes and mechanisms to disease-targeted therapies.  Pharmacol Rev. 2018 Jan;70(1):142–173. doi: 10.1124/pr.117.014456. PMID: 29263209; PMCID: PMC5738717. [PMC free article: PMC5738717] [PubMed: 29263209]
132. Papadopoulos T, Rhee HJ, Subramanian D, Paraskevopoulou F, Mueller R, Schultz C, Brose N, Rhee JS, Betz H.  Endosomal phosphatidylinositol 3-phosphate promotes gephyrin clustering and GABAergic neurotransmission at inhibitory postsynapses.  J Biol Chem. 2017 Jan 27;292(4):1160–1177. doi: 10.1074/jbc.M116.771592. Epub 2016 Dec 9. PMID: 27941024; PMCID: PMC5270463. [PMC free article: PMC5270463] [PubMed: 27941024]
133. Papadopoulos T, Schemm R, Grubmüller H, Brose N.  Lipid binding defects and perturbed synaptogenic activity of a Collybistin R290H mutant that causes epilepsy and intellectual disability.  J Biol Chem. 2015 Mar 27;290(13):8256–70. doi: 10.1074/jbc.M114.633024. Epub 2015 Feb 12. PMID: 25678704; PMCID: PMC4375481. [PMC free article: PMC4375481] [PubMed: 25678704]
134. Pelkey KA, Chittajallu R, Craig MT, Tricoire L, Wester JC, McBain CJ.  Hippocampal GABAergic inhibitory interneurons.  Physiol Rev. 2017 Oct 1;97(4):1619–1747. doi: 10.1152/physrev.00007.2017. PMID: 28954853; PMCID: PMC6151493. [PMC free article: PMC6151493] [PubMed: 28954853]
135. Peng Z, Huang CS, Stell BM, Mody I, Houser CR. Altered expression of the δ subunit of the GABA_A receptor in a mouse model of temporal lobe epilepsy. J Neurosci. 2004 Sep 29;24(39):8629–39. doi: 10.1523/JNEUROSCI.2877-04.2004. PMID: 15456836; PMCID: PMC6729896. [PMC free article: PMC6729896] [PubMed: 15456836]
136. Petrou S, Reid C. The GABA_A  γ2(R43Q) mouse model of human genetic epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 731–739.
137. Pirker S, Schwarzer C, Czech T, Baumgartner C, Pockberger H, Maier H, Hauer B, Sieghart W, Furtinger S, Sperk G. Increased expression of GABA_A receptor β-subunits in the hippocampus of patients with temporal lobe epilepsy. J Neuropathol Exp Neurol. 2003 Aug;62(8):820–34. doi: 10.1093/jnen/62.8.820. PMID: 14503638. [PubMed: 14503638]
138. Quilichini PP, Chiron C, Ben-Ari Y, Gozlan H.  Stiripentol, a putative antiepileptic drug, enhances the duration of opening of GABA-A receptor channels.  Epilepsia. 2006 Apr;47(4):704–16. doi: 10.1111/j.1528-1167.2006.00497.x. PMID: 16650136. [PubMed: 16650136]
139. Ralvenius WT, Acuña MA, Benke D, Matthey A, Daali Y, Rudolph U, Desmeules J, Zeilhofer HU, Besson M. The clobazam metabolite N-desmethyl clobazam is an α2 preferring benzodiazepine with an improved therapeutic window for antihyperalgesia. Neuropharmacology. 2016 Oct;109:366–375. doi: 10.1016/j.neuropharm.2016.07.004. Epub 2016 Jul 5. PMID: 27392635; PMCID: PMC4981430. [PMC free article: PMC4981430] [PubMed: 27392635]
140. Reddy DS, Rogawski MA., Neurosteroids—Endogenous regulators of seizure susceptibility and role in the treatment of epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 984–1002.
141. Reynolds DS, Rosahl TW, Cirone J, O’Meara GF, Haythornthwaite A, Newman RJ, Myers J, Sur C, Howell O, Rutter AR, Atack J, Macaulay AJ, Hadingham KL, Hutson PH, Belelli D, Lambert JJ, Dawson GR, McKernan R, Whiting PJ, Wafford KA. Sedation and anesthesia mediated by distinct GABA_A receptor isoforms. J Neurosci. 2003 Sep 17;23(24):8608–17. doi: 10.1523/JNEUROSCI.23-24-08608.2003. PMID: 13679430; PMCID: PMC6740367. [PMC free article: PMC6740367] [PubMed: 13679430]
142. Rho JM, Donevan SD, Rogawski MA. Direct activation of GABA_A receptors by barbiturates in cultured rat hippocampal neurons. J Physiol. 1996 Dec 1;497(Pt 2)(Pt 2):509–22. doi: 10.1113/jphysiol.1996.sp021784. PMID: 8961191; PMCID: PMC1161000. [PMC free article: PMC1161000] [PubMed: 8961191]
143. Ribak CE, Shapiro LA, Yan XX, Dashtipour K, Nadler JV, Obenaus A, Spigelman I, Buckmaster PS.  Seizure-induced formation of basal dendrites on granule cells of the rodent dentate gyrus. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 484–493.
144. Rivas FM, Stables JP, Murphree L, Edwankar RV, Edwankar CR, Huang S, Jain HD, Zhou H, Majumder S, Sankar S, Roth BL, Ramerstorfer J, Furtmüller R, Sieghart W, Cook JM. Antiseizure activity of novel γ-aminobutyric acidA receptor subtype-selective benzodiazepine analogues in mice and rat models. J Med Chem. 2009 Apr 9;52(7):1795–8. doi: 10.1021/jm801652d. PMID: 19275170; PMCID: PMC2671240. [PMC free article: PMC2671240] [PubMed: 19275170]
145. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy J-M, Martin JR, Bluethmann H, Möhler H. Benzodiazepine actions mediated by specific γ- aminobutyric acidA receptor subtypes. Nature. 1999 Oct 21;401(6755):796–800. doi: 10.1038/44579. Erratum in: Nature 2000 Apr 6;404(6778):629. PMID: 10548105. [PubMed: 10548105]
146. Rudolph U, Knoflach F. Beyond classical benzodiazepines: novel therapeutic potential of GABA_A receptor subtypes. Nat Rev Drug Discov. 2011 Jul 29;10(9):685–97. doi: 10.1038/nrd3502. PMID: 21799515; PMCID: PMC3375401. [PMC free article: PMC3375401] [PubMed: 21799515]
147. Rudolph U, Möhler H. Analysis of GABA_A receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol. 2004;44:475–98. doi: 10.1146/annurev.pharmtox.44.101802.121429. PMID: 14744255. [PubMed: 14744255]
148. Sawyer GW, Chiara DC, Olsen RW, Cohen JB. Identification of the bovine γ-aminobutyric acid type A receptor α subunit residues photolabeled by the imidazobenzodiazepine [³H]Ro15-4513. J Biol Chem. 2002 Dec 20;277(51):50036–45. doi: 10.1074/jbc.M209281200. Epub 2002 Oct 17. PMID: 12388542. [PubMed: 12388542]
149. Schwarzer C, Tsunashima K, Wanzenböck C, Fuchs K, Sieghart W, Sperk G. GABA_A receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy. Neuroscience. 1997 Oct;80(4):1001–17. doi: 10.1016/s0306-4522(97)00145-0. PMID: 9284056. [PubMed: 9284056]
150. Sequeira A, Shen K, Gottlieb A, Limon A. Human brain transcriptome analysis finds region- and subject-specific expression signatures of GABA_A R subunits. Commun Biol. 2019 May 1;2:153. doi: 10.1038/s42003-019-0413-7. PMID: 31069263; PMCID: PMC6494906. [PMC free article: PMC6494906] [PubMed: 31069263]
151. Shen D, Hernandez CC, Shen W, Hu N, Poduri A, Shiedley B, Rotenberg A, Datta AN, Leiz S, Patzer S, Boor R, Ramsey K, Goldberg E, Helbig I, Ortiz-Gonzalez XR, Lemke JR, Marsh ED, Macdonald RL.  De novo GABRG2 mutations associated with epileptic encephalopathies. Brain. 2017 Jan;140(1):49–67. doi: 10.1093/brain/aww272. Epub 2016 Nov 17. PMID: 27864268; PMCID: PMC5226060. [PMC free article: PMC5226060] [PubMed: 27864268]
152. Siegwart R, Jurd R, Rudolph U. Molecular determinants for the action of general anesthetics at recombinant α2β3γ2 γ-aminobutyric acidA receptors. J Neurochem. 2002 Jan;80(1):140–8. doi: 10.1046/j.0022-3042.2001.00682.x. PMID: 11796752. [PubMed: 11796752]
153. Sigel E, Ernst M. The benzodiazepine binding sites of GABA_A receptors. Trends Pharmacol Sci. 2018 Jul;39(7):659–671. doi: 10.1016/j.tips.2018.03.006. Epub 2018 Apr 30. PMID: 29716746. [PubMed: 29716746]
154. Snead OC 3rd.  Pharmacological models of generalized absence seizures in rodents.  J Neural Transm Suppl.  1992;35:7–19. doi: 10.1007/978-3-7091-9206-1_2. PMID: 1380980. [PubMed: 1380980]
155. Sloviter RS, Bumanglag AV, Schwarcz R, Frotscher M.  Abnormal dentate gyrus network circuitry in temporal lobe epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 454–469. [PubMed: 22787603]
156. Solomon VR, Tallapragada VJ, Chebib M, Johnston GAR, Hanrahan JR.  GABA allosteric modulators: An overview of recent developments in non-benzodiazepine modulators.  Eur J Med Chem. 2019 Jun 1;171:434–461. doi: 10.1016/j.ejmech.2019.03.043. Epub 2019 Mar 23. PMID: 30928713. [PubMed: 30928713]
157. Sorokin JM, Davidson TJ, Frechette E, Abramian AM, Deisseroth K, Huguenard JR, Paz JT.  Bidirectional control of generalized epilepsy networks via rapid real-time switching of firing mode.  Neuron. 2017 Jan 4;93(1):194–210. doi: 10.1016/j.neuron.2016.11.026. Epub 2016 Dec 15. PMID: 27989462; PMCID: PMC5268077. [PMC free article: PMC5268077] [PubMed: 27989462]
158. Sills GJ, Rogawski MA.  Mechanisms of action of currently used antiseizure drugs.  Neuropharmacology. 2020 May 15;168:107966. doi: 10.1016/j.neuropharm.2020.107966. Epub 2020 Jan 14. PMID: 32120063. [PubMed: 32120063]
159. Sun C, Zhu H, Clark S, Gouaux E. Cryo-EM structures reveal native GABAA receptor assemblies and pharmacology.  Nature. 2023 Oct;622(7981):195-201. doi: 10.1038/s41586-023-06556-w. Epub 2023 Sep 20. PMID: 37730991; PMCID: PMC10550821. [PMC free article: PMC10550821] [PubMed: 37730991]
160. Suzuki S, Rogawski MA.  T-type calcium channels mediate the transition between tonic and phasic firing in thalamic neurons.  Proc Natl Acad Sci U S A. 1989 Sep;86(18):7228–32. doi: 10.1073/pnas.86.18.7228. PMID: 2550936; PMCID: PMC298030. [PMC free article: PMC298030] [PubMed: 2550936]
161. Tanaka M, DeLorey TM, Delgado-Escueta AV, Olsen RW.  GABRB3, epilepsy, and neurodevelopment. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 887–899.
162. Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, Castro-Ortega R, Martinez-Juarez IE, Pascual-Castroviejo I, Machado-Salas J, Silva R, Bailey JN, Bai D, Ochoa A, Jara-Prado A, Pineda G, Macdonald RL, Delgado-Escueta AV.  Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy.  Am J Hum Genet. 2008 Jun;82(6):1249–61. doi: 10.1016/j.ajhg.2008.04.020. PMID: 18514161; PMCID: PMC2427288. [PMC free article: PMC2427288] [PubMed: 18514161]
163. Treiman DM.  GABAergic mechanisms in epilepsy.  Epilepsia.  2001;42 Suppl 3:8–12. doi: 10.1046/j.1528-1157.2001.042suppl.3008.x. PMID: 11520315. [PubMed: 11520315]
164. Tyagarajan SK, Fritschy J-M. Gephyrin: a master regulator of neuronal function? Nat Rev Neurosci. 2014 Mar;15(3):141–56. doi: 10.1038/nrn3670. PMID: 24552784. [PubMed: 24552784]
165. Walker MC, Kullmann DM. Tonic GABA_A  receptor-mediated signaling in epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper’s basic mechanisms of the epilepsies, 4th edition. Oxford University Press; 2012. p. 111–121.
166. Walker MC, Kullmann DM.  Optogenetic and chemogenetic therapies for epilepsy.  Neuropharmacology. 2020 May 15;168:107751. doi: 10.1016/j.neuropharm.2019.107751. Epub 2019 Sep 5. PMID: 31494141. [PubMed: 31494141]
167. Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, Williams DA, Sutherland GR, Mulley JC, Scheffer IE, Berkovic SF. Mutant GABA_A receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001 May;28(1):49–52. doi: 10.1038/ng0501-49. PMID: 11326275. [PubMed: 11326275]
168. Wallner M, Hanchar HJ, Olsen RW. Alcohol selectivity of β3-containing GABA_A receptors: evidence for a unique extracellular alcohol/imidazobenzodiazepine Ro15–4513 binding site at the α+β- subunit interface in αβ3δ GABA_A receptors. Neurochem Res. 2014 Jun;39(6):1118–26. doi: 10.1007/s11064-014-1243-0. Epub 2014 Feb 6. PMID: 24500446; PMCID: PMC4114768. [PMC free article: PMC4114768] [PubMed: 24500446]
169. Walters RJ, Hadley SH, Morris KD, Amin J. Benzodiazepines act on GABA_A receptors via two distinct and separable mechanisms. Nat Neurosci. 2000 Dec;3(12):1274–81. doi: 10.1038/81800. PMID: 11100148. [PubMed: 11100148]
170. Wang DS, Orser BA.  Inhibition of learning and memory by general anesthetics.  Can J Anaesth. 2011 Feb;58(2):167–77. doi: 10.1007/s12630-010-9428-8. Epub 2010 Dec 23. PMID: 21181566. [PubMed: 21181566]
171. Wang H, Bedford FK, Brandon NJ, Moss SJ, Olsen RW. GABA_A-receptor-associated protein links GABA_A receptors and the cytoskeleton. Nature. 1999 Jan 7;397(6714):69–72. doi: 10.1038/16264. PMID: 9892355. [PubMed: 9892355]
172. Wang L, Covey DF, Akk G, Evers AS. Neurosteroid modulation of GABA_A receptor function by independent action at multiple specific binding sites. Curr Neuropharmacol.  2022;20(5):886–890. doi: 10.2174/1570159X19666211202150041. PMID: 34856904. [PMC free article: PMC9881108] [PubMed: 34856904]
173. Wang N, Lian J, Cao Y, Muheyati A, Yuan S, Ma Y, Zhang S, Yu G, Su R. High-dose benzodiazepines positively modulate GABA_A receptors via a flumazenil-insensitive mechanism. Int J Mol Sci. 2021b Dec 21;23(1):42. doi: 10.3390/ijms23010042. PMID: 35008465; PMCID: PMC8744940. [PMC free article: PMC8744940] [PubMed: 35008465]
174. Whiting PJ. GABA_A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discov Today. 2003 May 15;8(10):445–50. doi: 10.1016/s1359-6446(03)02703-x. PMID: 12801796. [PubMed: 12801796]
175. Witkin JM, Smith JL, Ping X, Gleason SD, Poe MM, Li G, Jin X, Hobbs J, Schkeryantz JM, McDermott JS, Alatorre AI, Siemian JN, Cramer JW, Airey DC, Methuku KR, Tiruveedhula VVNPB, Jones TM, Crawford J, Krambis MJ, Fisher JL, Cook JM, Cerne R. Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABA_A receptors: Improved bioavailability enhances anticonvulsant efficacy. Neuropharmacology. 2018 Jul 15;137:332–343. doi: 10.1016/j.neuropharm.2018.05.006. Epub 2018 May 3. PMID: 29778948. [PubMed: 29778948]
176. Wu M, Tian HL, Liu X, Lai JHC, Du S, Xia J.  Impairment of inhibitory synapse formation and motor behavior in mice lacking the NL2 binding partner LHFPL4/GARLH4.  Cell Rep. 2018 May 8;23(6):1691–1705. doi: 10.1016/j.celrep.2018.04.015. PMID: 29742426. [PubMed: 29742426]
177. Xu NZ, Ernst M, Treven M, Cerne R, Wakulchik M, Li X, Jones TM, Gleason SD, Morrow D, Schkeryantz JM, Rahman MT, Li G, Poe MM, Cook JM, Witkin JM. Negative allosteric modulation of alpha 5-containing GABA_A receptors engenders antidepressant-like effects and selectively prevents age-associated hyperactivity in tau-depositing mice. Psychopharmacology (Berl). 2018 Apr;235(4):1151–1161. doi: 10.1007/s00213-018-4832-9. Epub 2018 Jan 26. PMID: 29374303. [PubMed: 29374303]
178. Yamasaki T, Hoyos-Ramirez E, Martenson JS, Morimoto-Tomita M, Tomita S. GARLH family proteins stabilize GABA_A receptors at synapses. Neuron. 2017 Mar 8;93(5):1138–1152.e6. doi: 10.1016/j.neuron.2017.02.023. PMID: 28279354; PMCID: PMC5347473. [PMC free article: PMC5347473] [PubMed: 28279354]
179. Ye J, Zou G, Zhu R, Kong C, Miao C, Zhang M, Li J, Xiong W, Wang C. Structural basis of GABARAP-mediated GABA_A receptor trafficking and functions on GABAergic synaptic transmission. Nat Commun. 2021 Jan 12;12(1):297. doi: 10.1038/s41467-020-20624-z. PMID: 33436612; PMCID: PMC7803741. [PMC free article: PMC7803741] [PubMed: 33436612]
180. Zanos P, Nelson ME, Highland JN, Krimmel SR, Georgiou P, Gould TD, Thompson SM. A negative allosteric modulator for α5 subunit-containing GABA receptors exerts a rapid and persistent antidepressant-like action without the side effects of the NMDA receptor antagonist ketamine in mice. eNeuro.  2017 Mar 7;4(1):ENEURO.0285–16.2017. doi: 10.1523/ENEURO.0285-16.2017. PMID: 28275719; PMCID: PMC5334634. [PMC free article: PMC5334634] [PubMed: 28275719]
181. Zanotti A, Mariot R, Contarino A, Lipartiti M, Giusti P.  Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats.  Br J Pharmacol. 1996 Feb;117(4):647–52. doi: 10.1111/j.1476-5381.1996.tb15239.x. PMID: 8646409; PMCID: PMC1909353. [PMC free article: PMC1909353] [PubMed: 8646409]
182. Zeller A, Arras M, Jurd R, Rudolph U. Mapping the contribution of β3-containing GABA_A receptors to volatile and intravenous general anesthetic actions. BMC Pharmacol. 2007 Feb 24;7:2. doi: 10.1186/1471-2210-7-2. PMID: 17319964; PMCID: PMC1810244. [PMC free article: PMC1810244] [PubMed: 17319964]
183. Zolkowska D, Wu C-Y, Stone C, Rogawski MA.  Estimation of the intramuscular dose of midazolam in mice to achieve the therapeutic plasma concentration effective for the treatment of status epilepticus in humans (Abst 1.135).  American Epilepsy Society Annual Meeting, www​.aesnet.org, 2021