GABA-mediated Neurotransmission Research Articles

Functional interactions between potassium-chloride cotransporter (KCC) and inward rectifier potassium (Kir) channels in the insect central nervous system

The K+/Cl− cotransporter (KCC) is the primary mechanism by which mature neurons maintain low intracellular chloride (Cl−) concentration and has been shown to be functionally coupled to the GABA-gated chloride channels (GGCC) in Drosophila central neurons. Further, pharmacological inhibition of KCC has been shown to lead to acute toxicity of mosquitoes that highlights the toxicological relevance of insect KCC. Yet, gaps in knowledge remain regarding physiological drivers of KCC function and interactions of ion flux mechanisms upstream of GGCC in insects. Considering this, we employed electrophysiological and fluorescent microscopy techniques to further characterize KCC in the insect nervous system. Fluorescent microscopy indicated insect KCC2 is expressed in rdl neurons, which is the neuron type responsible for GABA-mediated neurotransmission, and are coexpressed with inward rectifier potassium (Kir) 2 channels. Coexpression of Kir2 and KCC2 suggested the possibility of functional coupling between these two K+ flux pathways. Indeed, extracellular recordings of Drosophila CNS showed pre-block of Kir channels prior to block of KCC led to a significant (P < 0.001) increase in CNS firing rates over baseline that when taken together, supports functional coupling of Kir to KCC function. Additionally, we documented a synergistic increase to toxicity of VU0463271, an established KCC inhibitor, above the expected additive toxicity after co-treatment with the Kir inhibitor, VU041. These data expand current knowledge regarding the physiological roles of KCC and Kir channels in the insect nervous system by defining additional pathways that facilitate inhibitory neurotransmission through GGCC.

Evaluation of site-selective drug effects on GABA receptors using nanovesicle-carbon nanotube hybrid devices

Site-selective drug effects on the ion-channel activities of γ-aminobutyric acid type A (GABAA) receptors are evaluated by using a nanovesicle-carbon nanotube hybrid device. Here, nanovesicles containing GABAA receptors are immobilized on the channel region of a carbon nanotube field-effect transistor. The receptor responses of this hybrid device to GABA are detected with a high sensitivity down to ∼1 aM even in the presence of other neurotransmitters. Further, sensitivity differences between two GABAA-receptor-subunit compositions of α5β2γ2 and α1β2γ2 are assessed by normalizing the dose-dependent responses obtained from these hybrid devices. Specifically, the GABA concentration that produces 50% of maximal response (EC50) is obtained as ∼10 pM for α5β2γ2 subunits and ∼1 nM for α1β2γ2 subunits of GABAA receptor. Significantly, the potency profiles of both antagonist and agonist of GABAA receptor can be evaluated by analyzing EC50 values in the presence and absence of those drugs. A competitive antagonist increases the EC50 value of GABA by binding to the same site as GABA, while an allosteric agonist reduces it by binding to a different site. These results indicate that this hybrid device can be a powerful tool for the evaluation of candidate drug substances modulating GABA-mediated neurotransmission.

Stop Signal Task Training Strengthens GABA-mediated Neurotransmission within the Primary Motor Cortex.

We have recently shown that the efficiency in stopping a response, measured using the stop signal task, is related to GABAA-mediated short-interval intracortical inhibition (SICI) in the primary motor cortex. In this study, we conducted two experiments on humans to determine whether training participants in the stop signal task within one session (Experiment 1) and across multiple sessions (Experiment 2) would increase SICI strength. For each experiment, we obtained premeasures and postmeasures of stopping efficiency and resting-state SICI, that is, during relaxed muscle activity (Experiment 1, n = 45, 15 male participants) and SICI during the stop signal task (Experiment 2, n = 44, 21 male participants). In the middle blocks of Experiment 1 and the middle sessions of Experiment 2, participants in the experimental group completed stop signal task training, whereas control participants completed a similar task without the requirement to stop a response. After training, the experimental group showed increased resting-state SICI strength (Experiment 1) and increased SICI strength during the stop signal task (Experiment 2). Although there were no overall behavioral improvements in stopping efficiency, improvements at an individual level were correlated with increases in SICI strength at rest (Experiment 1) and during successful stopping (Experiment 2). These results provide evidence of neuroplasticity in resting-state and task-related GABAA-mediated SICI in the primary motor cortex after response inhibition training. These results also suggest that SICI and stopping efficiency are temporally linked, such that a change in SICI between time points is correlated with a change in stopping efficiency between time points.

Ketogenic Diet Provided During Three Months Increases KCC2 Expression but Not NKCC1 in the Rat Dentate Gyrus.

Ketogenic diet, a high fat and low carbohydrate diet, has been used as a non-pharmacological treatment in refractory epilepsy since 1920. In recent years, it has demonstrated to be effective in the treatment of numerous neurological and non-neurological diseases. Some neurological and neuropsychiatric disorders are known to be caused by gamma-aminobutyric acid (GABA)-mediated neurotransmission dysfunction. The strength and polarity of GABA-mediated neurotransmission are determined by the intracellular chloride concentration, which in turn is regulated by cation-chloride cotransporters NKCC1 and KCC2. Currently, it is unknown if the effect of ketogenic diet is due to the modulation of these cotransporters. Thus, we analyzed the effect of a ketogenic diet on the cation-chloride cotransporters expression in the dentate gyrus. We estimated the total number of NKCC1 immunoreactive (NKCC1-IR) neuronal and glial cells by stereology and determined KCC2 labeling intensity by densitometry in the molecular and granule layers as well as in the hilus of dentate gyrus of rats fed with normal or ketogenic diet for 3 months. The results indicated that ketogenic diet provided during 3 months increased KCC2 expression, but not NKCC1 in the dentate gyrus of the rat. The significant increase of KCC2 expression could explain, at least in part, the beneficial effect of ketogenic diet in the diseases where the GABAergic system is altered by increasing its inhibitory efficiency.

Fluoxetine Suppresses Glutamate- and GABA-Mediated Neurotransmission by Altering SNARE Complex.

Major depressive disorder is one of the most common neuropsychiatric disorders worldwide. The treatment of choice that shows good efficacy in mood stabilization is based on selective serotonin reuptake inhibitors (SSRIs). Their primary mechanism of action is considered to be the increased synaptic concentration of serotonin through blockade of the serotonin transporter (SERT). In this study, we described an alternative mode of action of fluoxetine (FLX), which is a representative member of the SSRI class of antidepressants. We observed that FLX robustly decreases both glutamatergic and gamma-Aminobutyric acid (GABA)-ergic synaptic release in a SERT-independent manner. Moreover, we showed that this effect may stem from the ability of FLX to change the levels of main components of the SNARE (solubile N-ethylmaleimide-sensitive factor attachment protein receptor) complex. Our data suggest that this downregulation of SNARE fusion machinery involves diminished activity of protein kinase C (PKC) due to FLX-induced blockade of P/Q type of voltage-gated calcium channels (VGCCs). Taken together, by virtue of its inhibition at SERT, fluoxetine increases extracellular serotonin levels; however, at the same time, by reducing SNARE complex function, this antidepressant reduces glutamate and GABA release.

Anxiolytic-Like Effect of Methanol Leaf Extract of Laggera aurita Linn. F. (Asteraceae) in Mice

Background: Laggera aurita belongs to the Asteraceae family; it is an annual herb found growing as weeds in Sub-Saharan Africa, including Nigeria. In Nigeria, Laggera aurita is used as a remedy for paediatric malaria and in the management of epilepsy. Previous studies on extracts of this plant suggested its anticonvulsant activity via GABA-mediated neurotransmission. Therefore, this study aimed at evaluating anxiolytic-like effect of the plant extract. Methods: Anxiolytic potential of the methanol leaf extract of Laggera aurita was evaluated using staircase, elevated plus maze, hole board, open field, beam walking assay, and diazepam-induced sleep tests. Results: The extract significantly (P < 0.05) decreased the number of rearing in the staircase test at 600 and 300 mg/kg. In the elevated plus maze test, there was a significant (P < 0.05 at 600 and 300 mg/kg) increase in the total number of open arm entries and total time spent in the open arms (600 mg/kg). In the hole board test, the extract significantly (P ≤ 0.05 at 600mg/kg) decreased the number of head dips. Using the open field test, the axiolytic activity of the extract was further reflected by the significant (P < 0.05) decrease in the number of rearing (150, 300, and 600 mg/kg). The effect of the extract on beam walking assay showed a significant (P < 0.05) increase (600 mg/kg) in number of foot slips and time spent on beam. The extract (600 mg/kg) significantly (P < 0.05) increased the duration of sleep induced by diazepam. Conclusions: The results of this study revealed that the leaf extract of Laggera aurita possesses anxiolytic-like properties.

Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is a leading cause of inherited intellectual disability, and the most common known cause of autism spectrum disorder. FXS is broadly characterized by sensory hypersensitivity and several developmental alterations in synaptic and circuit function have been uncovered in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABA-mediated neurotransmission and fast-spiking (FS) GABAergic interneurons are central to cortical circuit development in the neonate. Here we demonstrate that there is a delay in the maturation of the intrinsic properties of FS interneurons in the sensory cortex, and a deficit in the formation of excitatory synaptic inputs on to these neurons in neonatal Fmr1 KO mice. Both these delays in neuronal and synaptic maturation were rectified by chronic administration of a TrkB receptor agonist. These results demonstrate that the maturation of the GABAergic circuit in the sensory cortex is altered during a critical developmental period due in part to a perturbation in BDNF-TrkB signaling, and could contribute to the alterations in cortical development underlying the sensory pathophysiology of FXS.SIGNIFICANCE STATEMENT Fragile X (FXS) individuals have a range of sensory related phenotypes, and there is growing evidence of alterations in neuronal circuits in the sensory cortex of the mouse model of FXS (Fmr1 KO). GABAergic interneurons are central to the correct formation of circuits during cortical critical periods. Here we demonstrate a delay in the maturation of the properties and synaptic connectivity of interneurons in Fmr1 KO mice during a critical period of cortical development. The delays both in cellular and synaptic maturation were rectified by administration of a TrkB receptor agonist, suggesting reduced BDNF-TrkB signaling as a contributing factor. These results provide evidence that the function of fast-spiking interneurons is disrupted due to a deficiency in neurotrophin signaling during early development in FXS.

Astrocytic GABA Transporters: Pharmacological Properties and Targets for Antiepileptic Drugs.

Inactivation of GABA-mediated neurotransmission is achieved by high-affinity transporters located at both GABAergic neurons and the surrounding astrocytes. Early studies of the pharmacological properties of neuronal and glial GABA transporters suggested that different types of transporters might be expressed in the two cell types, and such a scenario was confirmed by the cloning of four distinctly different GABA transporters from a number of different species. These GABA-transport entities have been extensively characterized using a large number of GABA analogues of restricted conformation, and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug. This review provides a detailed account of efforts to design new subtype-selective GABA-transport inhibitors aiming at identifying novel antiepileptic drug candidates.

ID 278 – Motor cortical disinhibition is more pronounced in Progressive Supranuclear Palsy than in Parkinson’s disease: Evidence from TMS

Objective Progressive Supranuclear Palsy-PSP is the second most common parkinsonian syndrome after Parkinson’s disease-PD. Non-invasive neurophysiological techniques, such as transcranial magnetic stimulation-TMS, could prove useful to gain insight into these pathologies and for differential diagnosis. Methods Seventeen PD, 13 PSP and 11 healthy controls-CT were included in this study. TMS evaluation included resting motor threshold-RMT, motor evoked potentials-MEP amplitude, response to inhibitory-SICI and facilitating-ICF conditioning stimuli, cortical-CSP and ipsilateral silent period-iSP. Statistical analysis was performed using either parametric or non-parametric ANOVA and post-hoc tests according to data distribution. Results PSP and PD groups did not significantly differ in UPDRS. RMT distributed differently across groups (p.008), with PSP patients showing highest values and PD lowest (PSPvs.PD p.002). Group also affected iSP duration (p.016), being longest in PSP and lowest in HC (PSPvs.CT p.005). On paired-pulse inhibition and facilitation, a significant effect for inter-stimulus interval-ISI ( p Conclusions This study suggests that TMS can help differentiate PD and PSP. PSP patients displayed different response to the perturbation induced by conditioning stimuli and iSP elongation, probably due to impairment of GABA-mediated neurotransmission.

GABAergic mRNA expression is upregulated in the prefrontal cortex of rats sensitized to methamphetamine

Inhibitory gamma-aminobutyric acid (GABA)-mediated neurotransmission plays an important role in the regulation of the prefrontal cortex (PFC), with increasing evidence suggesting that dysfunctional GABAergic processing of the PFC may underlie certain deficits reported across psychotic disorders. Methamphetamine (METH) is a psychostimulant that induces chronic psychosis in a subset of users, with repeat administration producing a progressively increased vulnerability to psychotic relapse following subsequent drug administration (sensitization). The aim here was to investigate changes to GABAergic mRNA expression in the PFC of rats sensitized to METH using quantitative polymerase chain reaction (qPCR). Male Sprague–Dawley rats (n=12) underwent repeated methamphetamine (intraperitoneal (i.p.) or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute methamphetamine (1mg/kg i.p.) and RNA was isolated from the PFC to compare the relative mRNA expression of a range of GABA enzymes, transporters and receptors subunits. METH challenge resulted in a significant sensitized behavioral (locomotor) response in METH pre-treated animals compared with saline pre-treated controls. The mRNAs of transporters (GAT1 and GAT3), ionotropic GABAA receptor subunits (α3 and β1), together with the metabotropic GABAB1 receptor, were upregulated in the PFC of sensitized rats compared with saline controls. These findings indicate that GABAergic mRNA expression is significantly altered at the pre and postsynaptic level following sensitization to METH, with sensitization resulting in the transcriptional upregulation of several inhibitory genes. These changes likely have significant consequences on GABA-mediated neurotransmission in the PFC and may underlie certain symptoms conserved across psychotic disorders, such as executive dysfunction.

GABAA currents are decreased by IL-1β in epileptogenic tissue of patients with temporal lobe epilepsy: implications for ictogenesis

Temporal lobe epilepsy (TLE) is the most prevalent form of adult focal onset epilepsy often associated with drug-resistant seizures. Numerous studies suggest that neuroinflammatory processes are pathologic hallmarks of both experimental and human epilepsy. In particular, the interleukin (IL)-1β/IL-1 receptor type 1 (R1) axis is activated in epileptogenic tissue, where it contributes significantly to the generation and recurrence of seizures in animal models. In this study, we investigated whether IL-1β affects the GABA-evoked currents (IGABA) in TLE tissue from humans. Given the limited availability of fresh human brain specimens, we used the “microtransplantation” method of injecting Xenopus oocytes with membranes from surgically resected hippocampal and cortical tissue from 21 patients with TLE and hippocampal sclerosis (HS), hippocampal tissue from five patients with TLE without HS, and autoptic and surgical brain specimens from 15 controls without epilepsy. We report the novel finding that pathophysiological concentrations of IL-1β decreased the IGABA amplitude by up to 30% in specimens from patients with TLE with or without HS, but not in control tissues. This effect was reproduced by patch-clamp recordings on neurons in entorhinal cortex slices from rats with chronic epilepsy, and was not observed in control slices. In TLE specimens from humans, the IL-1β effect was mediated by IL-1R1 and PKC. We also showed that IL-1R1 and IRAK1, the proximal kinase mediating the IL-1R1 signaling, are both up-regulated in the TLE compared with control specimens, thus supporting the idea that the IL-1β/IL-R1 axis is activated in human epilepsy. Our findings suggest a novel mechanism possibly underlying the ictogenic action of IL-1β, thus suggesting that this cytokine contributes to seizure generation in human TLE by reducing GABA-mediated neurotransmission.

Physical dependence liability of retigabine in rats

Aims: Retigabine (RTG) is an antiepileptic drug with a novel mechanism of action acting through the potentiation of KCNQ2/3 potassium channel, which are important in controlling neuronal excitability. In vitro evidence additionally suggests RTG augments GABA-mediated neurotransmission which may contribute a stabilizing effect on neuronal excitability. A key component in non-clinical abuse liability testing is the evaluation of a potential withdrawal syndrome induced by chronic administration, and abrupt cessation, of the test article. The objective of this study was to assess the potential of RTG to induce awithdrawal syndrome following abrupt cessation during chronic administration in Sprague Dawley rats. Methods: Rats were orally treated with 3, 10 and 30mg/kg/day RTG for 28 days and then observed for 14 days following the cessation of RTG treatment. Chlordiazepoxide HCl (CDP) was selected as the positive control. CDP was administered in incremental doses: 20mg/kg on Day 1, 40mg/kg on Day 2 and successive increments of 20mg/kg each day until the dose of 200mg/kgwas reached. This dose was then maintained to Day 28. Results: Following RTG cessation, no changes in body weight, food consumption or body temperature were observed and only some animals showed minor behavioural effects. Discontinuation of RTG after repeated administration induced a behavioural profile distinctly different from that observed following discontinuation of CDP. Conclusions: Whereas robust physiological and behavioural withdrawal symptoms were observed in the CDP-treated animals similar to that documented in the literature for benzodiazepines, the RTG-treated groups showed no withdrawal effects on physiological parameters and only a mild, non dose-dependent increase in behavioural parameters. Based on these findings, chronic administration of RTG in rats did not result in a withdrawal syndrome following abrupt discontinuation. Financial support: Authors did not received any financial support.

Polycomblike protein PHF1b: a transcriptional sensor for GABA receptor activity

BackgroundThe γ-aminobutyric acid (GABA) type A receptor (GABAAR) contains the recognition sites for a variety of agents used in the treatment of brain disorders, including anxiety and epilepsy. A better understanding of how receptor expression is regulated in individual neurons may provide novel opportunities for therapeutic intervention. Towards this goal we have studied transcription of a GABAAR subunit gene (GABRB1) whose activity is autologously regulated by GABA via a 10 base pair initiator-like element (β1-INR).MethodsBy screening a human cDNA brain library with a yeast one-hybrid assay, the Polycomblike (PCL) gene product PHD finger protein transcript b (PHF1b) was identified as a β1-INR associated protein. Promoter/reporter assays in primary rat cortical cells demonstrate that PHF1b is an activator at GABRB1, and chromatin immunoprecipitation assays reveal that presence of PHF1 at endogenous Gabrb1 is regulated by GABAAR activation.ResultsPCL is a member of the Polycomb group required for correct spatial expression of homeotic genes in Drosophila. We now show that PHF1b recognition of β1-INR is dependent on a plant homeodomain, an adjacent helix-loop-helix, and short glycine rich motif. In neurons, it co-immunoprecipitates with SUZ12, a key component of the Polycomb Repressive Complex 2 (PRC2) that regulates a number of important cellular processes, including gene silencing via histone H3 lysine 27 trimethylation (H3K27me3).ConclusionsThe observation that chronic exposure to GABA reduces PHF1 binding and H3K27 monomethylation, which is associated with transcriptional activation, strongly suggests that PHF1b may be a molecular transducer of GABAAR function and thus GABA-mediated neurotransmission in the central nervous system.

GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior.

Impaired GABA–mediated neurotransmission has been implicated in many neurologic diseases including epilepsy, intellectual disability, and psychiatric disorders. Here we report that inhibitory neuron transplantation into the hippocampus of adult mice with confirmed epilepsy at the time of grafting dramatically reduced the occurrence of electrographic seizures and restored behavioral deficits in spatial learning, hyperactivity, and the aggressive response to handling. In the recipient brain, GABA progenitors migrated up to 1500 μm from the injection site, expressed genes and proteins characteristic for interneurons, differentiated into functional inhibitory neurons, and received excitatory synaptic input. In contrast to hippocampus, cell grafts into basolateral amygdala rescued the hyperactivity deficit but did not alter seizure activity or other abnormal behaviors. Our results highlight a critical role for interneurons in epilepsy and suggest that interneuron cell transplantation is a powerful approach to halt seizures and rescue accompanying deficits in severely epileptic mice.

Autistic-like behaviour in Scn1a+/− mice and rescue by enhanced GABA-mediated neurotransmission

Haploinsufficiency of the SCN1A gene encoding voltage-gated sodium channel NaV1.1 causes Dravet Syndrome (DS), a childhood neuropsychiatric disorder including recurrent intractable seizures, cognitive deficit, and autism-spectrum behaviors. The neural mechanisms responsible for cognitive deficit and autism-spectrum behaviors in DS are poorly understood. Here we show that mice with Scn1a haploinsufficiency display hyperactivity, stereotyped behaviors, social interaction deficits, and impaired context-dependent spatial memory. Olfactory sensitivity is retained, but novel food odors and social odors are aversive to Scn1a+/− mice. GABAergic neurotransmission is specifically impaired by this mutation, and selective deletion of NaV1.1 channels in forebrain interneurons is sufficient to cause these behavioral and cognitive impairments. Remarkably, treatment with low-dose clonazepam, a positive allosteric modulator of GABAA receptors, completely rescued the abnormal social behaviors and deficits in fear memory in DS mice, demonstrating that they are caused by impaired GABAergic neurotransmission and not by neuronal damage from recurrent seizures. These results demonstrate a critical role for NaV1.1 channels in neuropsychiatric functions and provide a potential therapeutic strategy for cognitive deficit and autism-spectrum behaviors in DS.

Novel modulatory effects of neurosteroids and benzodiazepines on excitatory and inhibitory neurons excitability: a multi-electrode array recording study

The balance between glutamate- and GABA-mediated neurotransmission in the brain is fundamental in the nervous system, but it is regulated by the “tonic” release of a variety of endogenous factors. One such important group of molecules are the neurosteroids (NSs) which, similarly to benzodiazepines (BDZs), enhance GABAergic neurotransmission. The purpose of our work was to investigate, at in vivo physiologically relevant concentrations, the effects of NSs and BDZs as GABA modulators on dissociated neocortical neuron networks grown in long-term culture. We used a multi-electrode array (MEA) recording technique and a novel analysis that was able to both identify the action potentials of engaged excitatory and inhibitory neurons and to detect drug-induced network up-states (burst). We found that the NSs tetrahydrodeoxycorticosterone (THDOC) and allopregnanolone (ALLO) applied at low nanomolar concentrations, produced different modulatory effects on the two neuronal clusters. Conversely, at high concentrations (1 μM), both NSs, decreased excitatory and inhibitory neuron cluster excitability; however, even several hours after wash-out, the excitability of inhibitory neurons continued to be depressed, leading to a network long-term depression (LTD). The BDZs clonazepam (CLZ) and midazolam (MDZ) also decreased the network excitability, but only MDZ caused LTD of inhibitory neuron cluster. To investigate the origin of the LTD after MDZ application, we tested finasteride (FIN), an inhibitor of endogenous NSs synthesis. FIN did not prevent the LTD induced by MDZ, but surprisingly induced it after application of CLZ. The significance and possible mechanisms underlying these LTD effects of NSs and BDZs are discussed. Taken together, our results not only demonstrate that ex vivo networks show a sensitivity to NSs and BDZs comparable to that expressed in vivo, but also provide a new global in vitro description that can help in understanding their activity in more complex systems.

Neuroanatomical substrates involved in cannabinoid modulation of defensive responses

Administration of Cannabis sativa derivatives causes anxiolytic or anxiogenic effects in humans and laboratory animals, depending on the specific compound and dosage used. In agreement with these findings, several studies in the last decade have indicated that the endocannabinoid system modulates neuronal activity in areas involved in defensive responses. The mechanisms of these effects, however, are still not clear. The present review summarizes recent data suggesting that they involve modulation of glutamate and GABA-mediated neurotransmission in brain sites such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of the stria terminalis, hippocampus and dorsal periaqueductal gray. Moreover, we also discuss results indicating that, in these regions, the endocannabinoid system could be particularly engaged by highly stressful situations.

A Gut Feeling about GABA: Focus on GABAB Receptors

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the body and hence GABA-mediated neurotransmission regulates many physiological functions, including those in the gastrointestinal (GI) tract. GABA is located throughout the GI tract and is found in enteric nerves as well as in endocrine-like cells, implicating GABA as both a neurotransmitter and an endocrine mediator influencing GI function. GABA mediates its effects via GABA receptors which are either ionotropic GABAA or metabotropic GABAB. The latter which respond to the agonist baclofen have been least characterized, however accumulating data suggest that they play a key role in GI function in health and disease. Like GABA, GABAB receptors have been detected throughout the gut of several species in the enteric nervous system, muscle, epithelial layers as well as on endocrine-like cells. Such widespread distribution of this metabotropic GABA receptor is consistent with its significant modulatory role over intestinal motility, gastric emptying, gastric acid secretion, transient lower esophageal sphincter relaxation and visceral sensation of painful colonic stimuli. More intriguing findings, the mechanisms underlying which have yet to be determined, suggest GABAB receptors inhibit GI carcinogenesis and tumor growth. Therefore, the diversity of GI functions regulated by GABAB receptors makes it a potentially useful target in the treatment of several GI disorders. In light of the development of novel compounds such as peripherally acting GABAB receptor agonists, positive allosteric modulators of the GABAB receptor and GABA producing enteric bacteria, we review and summarize current knowledge on the function of GABAB receptors within the GI tract.

Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia

Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.

The transience of interneuron circuit diversity just “sped” up

Understanding the diversity of inhibitory neurotransmission is a central issue in neuroscience. GABA-mediated neurotransmission takes place across a broad time scale (Fig. 1). Fast GABAA receptor-mediated phasic inhibition decays within milliseconds, whereas tonic GABAA receptor-mediated inhibition persists for seconds and longer. Between these ends of the spectrum, there are the more enigmatic slow GABAA-mediated phasic inhibition [GABAA,slow (1)] and inhibition mediated by the GABAB receptor. GABAA,slow is poorly understood. The time course of decay is on a time scale of tens of milliseconds, intermediate to fast phasic inhibition and GABAB-mediated inhibition. The work of Szabadics et al. (2) in a recent issue of PNAS sheds light on the mechanism of GABAA,slow in cortical pyramidal cells (PCs) and also provides evidence for additional diversity of interneuron circuits in the cortex.