Γ-aminobutyric Acid Signaling Research Articles

Status epilepticus: Is there a Stage 1 plus?

In status epilepticus (SE), "time is brain." Currently, first-line therapy consists of benzodiazepines (BDZs) and SE is classified by the response to treatment; stage 2 or established SE is defined as "BDZ-resistant SE." Nonetheless, this classification does not always work, especially in the case of prolonged convulsive SE, where many molecular changes occur and γ-aminobutyric acid signaling becomes excitatory. Under these circumstances, BDZ therapy might not be optimal, and might be possibly detrimental, if given alone; as the duration of SE increases, so too does BDZresistance. Murine models of SE showed how these cases might benefit more from synergistic combined therapy from the start. The definition of Stage 1 plus is suggested, as a stage requiring combined therapy from the start, which includes prolonged SE with seizure activity going on for >10 min, the time that marks the disruption of receptor homeostasis, with increased internalization. This specific stage might require a synergistic approach from the start, with a combination of first- and second-line treatment.

Identification of Molecular Mechanisms of Ameloblastoma and Drug Repositioning by Integration of Bioinformatics Analysis and Molecular Docking Simulation.

Ameloblastoma (AM) is a benign tumor locally originated from odontogenic epithelium that is commonly found in the jaw. This tumor makes aggressive invasions and has a high recurrence rate. This study aimed to investigate the differentially expressed genes (DEGs), biological function alterations, disease targets, and existing drugs for AM using bioinformatics analysis. The data set of AM was retrieved from the GEO database (GSE132474) and identified the DEGs using bioinformatics analysis. The biological alteration analysis was applied to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Protein-protein interaction (PPI) network analysis and hub gene identification were screened through NetworkAnalyst. The transcription factor-protein network was constructed via OmicsNet. We also identified candidate compounds from L1000CDS2 database. The target of AM and candidate compounds were verified using docking simulation. Totally, 611 DEGs were identified. The biological function enrichment analysis revealed glycosaminoglycan and GABA (γ-aminobutyric acid) signaling were most significantly up-regulated and down-regulated in AM, respectively. Subsequently, hub genes and transcription factors were screened via the network and showed FOS protein was found in both networks. Furthermore, we evaluated FOS protein to be a therapeutic target in AMs. Candidate compounds were screened and verified using docking simulation. Tanespimycin showed the greatest affinity binding value to bind FOS protein. This study presented the underlying molecular mechanisms of disease pathogenesis, biological alteration, and important pathways of AMs and provided a candidate compound, Tanespimycin, targeting FOS protein for the treatment of AMs.

Effects of OsomeFood Clean Label plant-based meals on the gut microbiome

BackgroundPlant-based diets offer more beneficial microbes and can modulate gut microbiomes to improve human health. We evaluated the effects of the plant-based OsomeFood Clean Label meal range (‘AWE’ diet), on the human gut microbiome.MethodsOver 21 days, ten healthy participants consumed OsomeFood meals for five consecutive weekday lunches and dinners and resumed their regular diets for other days/meals. On follow-up days, participants completed questionnaires to record satiety, energy and health, and provided stool samples. To document microbiome variations and identify associations, species and functional pathway annotations were analyzed by shotgun sequencing. Shannon diversity and regular diet calorie intake subsets were also assessed.ResultsOverweight participants gained more species and functional pathway diversity than normal BMI participants. Nineteen disease-associated species were suppressed in moderate-responders without gaining diversity, and in strong-responders with diversity gains along with health-associated species. All participants reported improved short-chain fatty acids production, insulin and γ-aminobutyric acid signaling. Moreover, fullness correlated positively with Bacteroides eggerthii; energetic status with B. uniformis, B. longum, Phascolarctobacterium succinatutens, and Eubacterium eligens; healthy status with Faecalibacterium prausnitzii, Prevotella CAG 5226, Roseburia hominis, and Roseburia sp. CAG 182; and overall response with E. eligens and Corprococcus eutactus. Fiber consumption was negatively associated with pathogenic species.ConclusionAlthough the AWE diet was consumed for only five days a week, all participants, especially overweight ones, experienced improved fullness, health status, energy and overall responses. The AWE diet benefits all individuals, especially those of higher BMI or low-fiber consumption.

Transcriptomic Mapping of Neurotoxicity Pathways in the Rat Brain in Response to Intraventricular Polymyxin B.

Intraventricular or intrathecal administration of polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria caused infections in the central nervous system (CNS). However, our limited knowledge of the mechanisms underpinning polymyxin-induced neurotoxicity significantly hinders the development of safe and efficacious polymyxin dosing regimens. To this end, we conducted transcriptomic analyses of the rat brain and spinal cord 1h following intracerebroventricular administration of polymyxin B into rat lateral ventricle at a clinically relevant dose (0.5mg/kg). Following the treatment, 66 differentially expressed genes (DEGs) were identified in the brain transcriptome while none for the spinal cord (FDR ≤ 0.05, fold-change ≥ 1.5). DEGs were enriched in signaling pathways associated with hormones and neurotransmitters, including dopamine and (nor)epinephrine. Notably, the expression levels of Slc6a3 and Gabra6 were decreased by 20-fold and 4.3-fold, respectively, likely resulting in major perturbations of dopamine and γ-aminobutyric acid signaling in the brain. Mass spectrometry imaging of brain sections revealed a distinct pattern of polymyxin B distribution with the majority accumulating in the injection-side lateral ventricle and subsequently into third and fourth ventricles. Polymyxin B was not detectable in the left lateral ventricle or brain tissue. Electrophysiological measurements on primary cultured rat neurons revealed a large inward current and significant membrane leakage following polymyxin B treatment. Our work demonstrates, for the first time, the key CNS signaling pathways associated with polymyxin neurotoxicity. This mechanistic insight combined with pharmacokinetic/pharmacodynamic dosing strategies will help guide the design of safe and effective intraventricular/intrathecal polymyxin treatment regimens for CNS infections caused by MDR Gram-negative pathogens.

The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics.

There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS's resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.

From bench to bedside: The mGluR5 system in people with and without Autism Spectrum Disorder and animal model systems

The metabotropic glutamate receptor 5 (mGluR5) is a key regulator of excitatory (E) glutamate and inhibitory (I) γ-amino butyric acid (GABA) signalling in the brain. Despite the close functional ties between mGluR5 and E/I signalling, no-one has directly examined the relationship between mGluR5 and glutamate or GABA in vivo in the human brain of autistic individuals. We measured [18F] FPEB (18F-3-fluoro-5-[(pyridin-3-yl)ethynyl]benzonitrile) binding in 15 adults (6 with Autism Spectrum Disorder) using two regions of interest, the left dorsomedial prefrontal cortex and a region primarily composed of left striatum and thalamus. These two regions were mapped out using MEGA-PRESS voxels and then superimposed on reconstructed PET images. This allowed for direct comparison between mGluR5, GABA + and Glx. To better understand the molecular underpinnings of our results we used an autoradiography study of mGluR5 in three mouse models associated with ASD: Cntnap2 knockout, Shank3 knockout, and 16p11.2 deletion. Autistic individuals had significantly higher [18F] FPEB binding (t (13) = −2.86, p = 0.047) in the left striatum/thalamus region of interest as compared to controls. Within this region, there was a strong negative correlation between GABA + and mGluR5 density across the entire cohort (Pearson’s correlation: r (14) = −0.763, p = 0.002). Cntnap2 KO mice had significantly higher mGlu5 receptor binding in the striatum (caudate-putamen) as compared to wild-type (WT) mice (n = 15, p = 0.03). There were no differences in mGluR5 binding for mice with the Shank3 knockout or 16p11.2 deletion. Given that Cntnap2 is associated with a specific striatal deficit of parvalbumin positive GABA interneurons and ‘autistic’ features, our findings suggest that an increase in mGluR5 in ASD may relate to GABAergic interneuron abnormalities.

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects reciprocal social interaction and produces abnormal repetitive, restrictive behaviors and interests. The diverse causes of ASD are divided into genetic alterations and environmental risks. The prevalence of ASD has been rising for several decades, which might be related to environmental risks as it is difficult to consider that the prevalence of genetic disorders related to ASD would increase suddenly. The latter includes (1) exposure to medications, such as valproic acid (VPA) and selective serotonin reuptake inhibitors (SSRIs) (2), maternal complications during pregnancy, including infection and hypertensive disorders of pregnancy, and (3) high parental age. Epidemiological studies have indicated a pathogenetic role of prenatal exposure to VPA and maternal inflammation in the development of ASD. VPA is considered to exert its deleterious effects on the fetal brain through several distinct mechanisms, such as alterations of γ-aminobutyric acid signaling, the inhibition of histone deacetylase, the disruption of folic acid metabolism, and the activation of mammalian target of rapamycin. Maternal inflammation that is caused by different stimuli converges on a higher load of proinflammatory cytokines in the fetal brain. Rodent models of maternal exposure to SSRIs generate ASD-like behavior in offspring, but clinical correlations with these preclinical findings are inconclusive. Hypertensive disorders of pregnancy and advanced parental age increase the risk of ASD in humans, but the mechanisms have been poorly investigated in animal models. Evidence of the mechanisms by which environmental factors are related to ASD is discussed, which may contribute to the development of preventive and therapeutic interventions for ASD.

Nitric oxide mediates γ-aminobutyric acid signaling to regulate phenolic compounds biosynthesis in soybean sprouts under NaCl stress

Salt stress is an effective way to enhance the accumulation of phenolic compounds in soybean sprouts. In the present study, the effects of nitric oxide (NO) and γ-aminobutyric acid (GABA) on the biosynthesis of phenolic compounds in soybean sprouts under NaCl stress were investigated. Results showed that activities of three key enzymes involved in the biosynthesis of phenolic compounds increased by 27%–55% when the exogenous donor of NO was applied. As a result, the concentration of total phenolic compounds, phenolic acids and isoflavones in sprouts under NaCl stress increased by 26.64%, 10.91% and 19.14%, respectively. In addition, both N-nitro-L-arginine methyl ester (L-NAME) and sodium tungstate treatment inhibited the synthesis of NO in soybean sprouts under NaCl stress, which lead to the decrease of phenolics content. Treatment of GABA can alleviate the inhibition of L-NAME on phenolics biosynthesis by enhancing the production of NO. On the other hand, NO treatment can also alleviate the inhibition of 3-mercaptopropionic acid, the inhibitor of GABA synthesis, on the biosynthesis of phenolic compounds. To conclude, both NO and GABA can enhance the biosynthesis of phenolic compounds in soybean sprouts and NO can mediate the promoting effect of GABA.

The Alteration of Chloride Homeostasis/GABAergic Signaling in Brain Disorders: Could Oxidative Stress Play a Role?

In neuronal precursors and immature neurons, the depolarizing (excitatory) effect of γ-Aminobutyric acid (GABA) signaling is associated with elevated [Cl−]i; as brain cells mature, a developmental switch occurs, leading to the decrease of [Cl−]i and to the hyperpolarizing (inhibitory) effect of GABAergic signaling. [Cl−]i is controlled by two chloride co-transporters: NKCC1, which causes Cl− to accumulate into the cells, and KCC2, which extrudes it. The ontogenetic upregulation of the latter determines the above-outlined switch; however, many other factors contribute to the correct [Cl−]i in mature neurons. The dysregulation of chloride homeostasis is involved in seizure generation and has been associated with schizophrenia, Down’s Syndrome, Autism Spectrum Disorder, and other neurodevelopmental disorders. Recently, much effort has been put into developing new drugs intended to inhibit NKCC1 activity, while no attention has been paid to the origin of [Cl−]i dysregulation. Our study examines the pathophysiology of Cl− homeostasis and focuses on the impact of oxidative stress (OS) and inflammation on the activity of Cl− co-transporters, highlighting the relevance of OS in numerous brain abnormalities and diseases. This hypothesis supports the importance of primary prevention during pregnancy. It also integrates the therapeutic framework addressed to restore normal GABAergic signaling by counteracting the alteration in chloride homeostasis in central nervous system (CNS) cells, aiming at limiting the use of drugs that potentially pose a health risk.

Axonal Modulation of Striatal Dopamine Release by Local γ-Aminobutyric Acid (GABA) Signalling.

Striatal dopamine (DA) release is critical for motivated actions and reinforcement learning, and is locally influenced at the level of DA axons by other striatal neurotransmitters. Here, we review a wealth of historical and more recently refined evidence indicating that DA output is inhibited by striatal γ-aminobutyric acid (GABA) acting via GABAA and GABAB receptors. We review evidence supporting the localisation of GABAA and GABAB receptors to DA axons, as well as the identity of the striatal sources of GABA that likely contribute to GABAergic modulation of DA release. We discuss emerging data outlining the mechanisms through which GABAA and GABAB receptors inhibit the amplitude as well as modulate the short-term plasticity of DA release. Furthermore, we highlight recent data showing that DA release is governed by plasma membrane GABA uptake transporters on striatal astrocytes, which determine ambient striatal GABA tone and, by extension, the tonic inhibition of DA release. Finally, we discuss how the regulation of striatal GABA-DA interactions represents an axis for dysfunction in psychomotor disorders associated with dysregulated DA signalling, including Parkinson’s disease, and could be a novel therapeutic target for drugs to modify striatal DA output.

Glyoxalase 1 Inhibitor Alleviates Autism-like Phenotype in a Prenatal Valproic Acid-Induced Mouse Model.

Autism spectrum disorder (ASD) is a severe neurological and developmental disorder that impairs a person's ability to socialize and communicate and affects behavior. The number of patients diagnosed with ASD has risen rapidly. However, the pathophysiology of ASD is poorly understood, and drugs for ASD treatment are strikingly limited. This study aims to evaluate the roles of glyoxalase 1 (GLO1)-methylglyoxal (MG)-γ-aminobutyric acid (GABA) signaling in ASD using a valproic acid (VPA)-induced animal model of autism. The GLO1 levels were analyzed by RT-qPCR and Western blot assay, and MG levels were measured with a Methylglyoxal Assay Kit. The open-field and sniff duration tests were used to assess the interest and anxiety of VPA mice. The three-chamber, marble-burying, and tail-flick tests were applied to determine the sociability, repetitive behavior, and nociceptive threshold of VPA mice. Our results demonstrated that increased GLO1 and decreased MG were observed in VPA mice. Administration of S-p-bromobenzylglutathione cyclopentyl diester (BrBzGCp2), a GLO1 inhibitor, was beneficial for alleviating anxiety, reducing repetitive behavior, and improving the impaired sociability and nociceptive threshold of VPA mice. BrBzGCp2 treatment may be developed as a promising therapeutic strategy for patients with ASD.

GABAB Receptor-Mediated PI3K/Akt Signaling Pathway Alleviates Oxidative Stress and Neuronal Cell Injury in a Rat Model of Alzheimer’s Disease

Oxidative stress has been implicated in Alzheimer's disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process. Reduction and remodeling of γ-aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD. To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures. We found that GABAB receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABAB receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway. Taken together, our results suggest that GABAB receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD.

Identification of potential crucial genes and molecular mechanisms in glioblastoma multiforme by bioinformatics analysis.

Glioblastoma multiforme (GBM) is the most common and malignant brain tumor of the adult central nervous system and is associated with poor prognosis. The present study aimed to identify the hub genes in GBM in order to improve the current understanding of the underlying mechanism of GBM. The RNA-seq data were downloaded from The Cancer Genome Atlas database. The edgeR package in R software was used to identify differentially expressed genes (DEGs) between two groups: Glioblastoma samples and normal brain samples. Gene Ontology (GO) functional enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed using Database for Annotation, Visualization and Integrated Discovery software. Additionally, Cytoscape and Search Tool for the Retrieval of Interacting Genes/Proteins tools were used for the protein-protein interaction network, while the highly connected modules were extracted from this network using the Minimal Common Oncology Data Elements plugin. Next, the prognostic significance of the candidate hub genes was analyzed using UALCAN. In addition, the identified hub genes were verified by reverse transcription-quantitative (RT-q) PCR. In total, 1,483 DEGs were identified between GBM and control samples, including 954 upregulated genes and 529 downregulated genes (P<0.01; fold-change >16) and these genes were involved in different GO terms and signaling pathways. Furthermore, CDK1, BUB1, BUB1B, CENPA and GNG3 were identified as key genes in the GBM samples. The UALCAN tool verified that higher expression level of CENPA was relevant to poorer overall survival rates. In conclusion, CDK1, BUB1, BUB1B, CENPA and GNG3 were found to be potential biomarkers for GBM. Additionally, ‘cell cycle’ and ‘γ-aminobutyric acid signaling’ pathways may serve a significant role in the pathogenesis of GBM.

The Effect of Protein-Rich Extract from Bombyx Batryticatus against Glutamate-Damaged PC12 Cells Via Regulating γ-Aminobutyric Acid Signaling Pathway.

Bombyx Batryticatus (BB) is a known traditional Chinese medicine (TCM) utilized to treat convulsions, epilepsy, cough, asthma, headaches, etc. in China for thousands of years. This study is aimed at investigating optimum extraction of protein-rich extracts from BB (BBPs) using response surface methodology (RSM) and exploring the protective effects of BBPs against nerve growth factor (NGF)-induced PC12 cells injured by glutamate (Glu) and their underlying mechanisms. The results indicated optimum process of extraction was as follows: extraction time 1.00 h, ratio of liquid to the raw material 3.80 mL/g and ultrasonic power 230.0 W. The cell viability of PC12 cells stimulated by Glu was determined by CCK-8 assay. The levels of γ-aminobutyric (GABA), interleukin-1β (IL-1β), interleukin-4 (IL-4), tumor necrosis factor-α (TNF-α), 5-hydroxytryptamine (5-HT) and glucocorticoid receptor alpha (GR) in PC12 cells were assayed by ELISA. Furthermore, the Ca2+ levels in PC12 cells were determined by flow cytometry analysis. Protein and mRNA expressions of GABAA-Rα1, NMDAR1, GAD 65, GAD 67, GAT 1 and GAT 3 in PC12 cells were evaluated by real-time polymerase chain reaction (RT-PCR) and Western blotting assays. Results revealed that BBPs decreased toxic effects due to Glu treatment and decreased Ca2+ levels in PC12 cells. After BBPs treatments, levels of GABA and 5-HT were increased and contents of TNF-α, IL-4 and IL-1β were decreased in NGF-induced PC12 cells injured by Glu. Moreover, BBPs up-regulated the expressions of GABAA-Rα1, GAD 65 and GAD 67, whereas down-regulated that of NMDAR1 GAT 1 and GAT 3. These findings suggested that BBPs possessed protective effects on NGF-induced PC12 cells injured by Glu via γ-Aminobutyric Acid (GABA) signaling pathways, which demonstrated that BBPs has potential anti-epileptic effect in vitro. These findings may be useful in the development of novel medicine for the treatment of epilepsy.

GABAA Receptor-Mediated Currents and Hormone mRNAs in Cells Expressing More Than One Hormone Transcript in Intact Human Pancreatic Islets.

In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-clamp current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio (<0.6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high (>1.2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific.

Zona incerta projection neurons and GABAergic and GLP-1 mechanisms in the nucleus accumbens are involved in the control of gastric function and food intake

ObjectiveOur aim was to explore the effect of γ-aminobutyric acid (GABA) signaling in the nucleus accumbens (NAc) on promoting gastric function and food intake through glucagon-like peptide 1 (GLP-1)-sensitive gastric distension (GD) neurons under the regulatory control of the zona incerta (ZI). MethodsGABA neuronal projections were traced using retrograde tracing following fluorescence immunohistochemistry. An extracellular electrophysiological recording method was used to observe the firing of neurons in the NAc. HPLC was used to quantify the GABA and glutamate levels in the NAc after electrical stimulation of the ZI. Gastric functions including gastric motility and secretion, as well as food intake, were measured after the administration of different concentrations of GABA in the NAc or electrical stimulation of the ZI. ResultsSome of the GABA-positive neurons arising from the ZI projected to the NAc. Some GABA-A receptor (GABA-AR)-immunoreactive neurons in the NAc were also positive for GLP-1 receptor (GLP-1R) immunoreactivity. The firing of most GLP-1-sensitive GD neurons was decreased by GABA infusion in the NAc. Intra-NAc GABA administration also promoted gastric function and food intake. The responses induced by GABA were partially blocked by the GABA-AR antagonist bicuculline (BIC) and weakened by the GLP-1R antagonist exendin 9–39 (Ex9). Electrical stimulation of the ZI changed the firing patterns of most GLP-1-sensitive GD neurons in the NAc and promoted gastric function and food intake. Furthermore, these excitatory effects induced by electrical stimulation of the ZI were weakened by preadministration of BIC in the NAc. ConclusionRetrograde tracing and immunohistochemical staining showed a GABAergic pathway from the ZI to the NAc. GABAergic and GLP-1 mechanisms in the NAc are involved in the control of gastric function and food intake. In addition, the interaction (direct or indirect) between the ZI and these NAc mechanisms is involved in the control of gastric function and food intake.

Ιn Vitro Screening of γ-Aminobutyric Acid and Autoinducer-2 Signalling in Lactic Acid Bacteria Exhibiting Probiotic Potential Isolated from Natural Black Conservolea Olives.

In the present study, 33 strains of lactic acid bacteria (LAB) previously isolated from natural black Conservolea olives were assessed for their probiotic potential in vitro, as well as for their autoinducer-2 (AI-2) activity under standard growth conditions and the production of γ-aminobutyric acid (GABA). The probiotic tests included the in vitro resistance to low pH and resistance to bile salts, the evaluation of bile salt hydrolase activity, as well as safety tests regarding their possible haemolytic activity and their antimicrobial activity against pathogens. The results indicated that 17 strains were able to survive in low pH and in the presence of bile, with 15 of them also exhibiting partial bile salt hydrolase activity. None of the strains exhibited haemolytic activity or inhibited the growth of any of the examined pathogens. Moreover, the strains displayed generally low AI-2 activity under the growth conditions tested, regardless of the species. Interestingly, in contrast to what has been found in most foods, none of the isolates were found to produce GABA after 48 h of growth. The results from the AI-2 activity and extracellular GABA detection were considered as unexpected for LAB with probiotic attributes.

Enhanced Na+ -K+ -2Cl- cotransporter 1 underlies motor dysfunction in huntington's disease.

Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease. We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the Eγ-aminobutyric acid in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed. Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh150Q/7Q mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of Eγ-aminobutyric acid was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice. Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.

A half century of γ-aminobutyric acid.

γ-aminobutyric acid has become one of the most widely known neurotransmitter molecules in the brain over the last 50 years, recognised for its pivotal role in inhibiting neural excitability. It emerged from studies of crustacean muscle and neurons before its significance to the mammalian nervous system was appreciated. Now, after five decades of investigation, we know that most neurons are γ-aminobutyric-acid-sensitive, it is a cornerstone of neural physiology and dysfunction to γ-aminobutyric acid signalling is increasingly documented in a range of neurological diseases. In this review, we briefly chart the neurodevelopment of γ-aminobutyric acid and its two major receptor subtypes: the γ-aminobutyric acidA and γ-aminobutyric acidB receptors, starting from the humble invertebrate origins of being an ‘interesting molecule’ acting at a single γ-aminobutyric acid receptor type, to one of the brain’s most important neurochemical components and vital drug targets for major therapeutic classes of drugs. We document the period of molecular cloning and the explosive influence this had on the field of neuroscience and pharmacology up to the present day and the production of atomic γ-aminobutyric acidA and γ-aminobutyric acidB receptor structures. γ-Aminobutyric acid is no longer a humble molecule but the instigator of rich and powerful signalling processes that are absolutely vital for healthy brain function.

A review on the role of γ-aminobutyric acid signaling pathway in autism spectrum disorder

The etiology and pathogenesis of autism spectrum disorder (ASD) are not yet clear. Studies have shown that there are many neurotransmitter abnormalities in children with ASD, mainly involving in glutamate, γ-aminobutyric acid (GABA), dopamine, 5-HT and oxytocin. The imbalance of excitatory glutamatergic neurotransmitters and inhibitory GABAergic neurotransmitters is closely related to the pathogenesis of ASD. Both animal model studies and clinical studies on ASD suggest that GABA signaling pathway may play an important role in the pathogenesis of ASD. This article reviews the research on the association between GABA signaling pathway and the pathogenesis of ASD to further explore the pathogenesis of ASD and provide theoretical basis for the treatment of ASD.