Structural insights into GABA transport inhibition using an engineered neurotransmitter transporter.

γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter, and its levels in the synaptic space are controlled by the GABA transporter isoforms (GATs). GATs are structurally related to biogenic amine transporters but display interactions with distinct inhibitors used as anti-epileptics. In this study, we engineer the binding pocket of Drosophila melanogaster dopamine transporter to resemble GAT1 and determine high-resolution X-ray structures of the modified transporter in the substrate-free state and in complex with GAT1 inhibitors NO711 and SKF89976a that are analogs of tiagabine, a medication prescribed for the treatment of partial seizures. We observe that the primary binding site undergoes substantial shifts in subsite architecture in the modified transporter to accommodate the two GAT1 inhibitors. We also observe that SKF89976a additionally interacts at an allosteric site in the extracellular vestibule, yielding an occluded conformation. Interchanging SKF89976a interacting residue in the extracellular loop 4 between GAT1 and dDAT suggests a role for this motif in the selective control of neurotransmitter uptake. Our findings, therefore, provide vital insights into the organizational principles dictating GAT1 activity and inhibition.

Dopamine enhances GABAA receptor-mediated current amplitude in a subset of intrinsically photosensitive retinal ganglion cells.

Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive nonimage-forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine [via the D1-type dopamine receptor (D1R)]) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both nonimage-forming and image-forming visual functions.NEW & NOTEWORTHY Neuromodulators such as dopamine are important regulators of retinal function. Here, we demonstrate that dopamine increases inhibitory inputs to intrinsically photosensitive retinal ganglion cells (ipRGCs), in addition to its previously established effect on intrinsic light responsiveness. This indicates that dopamine, in addition to its ability to intrinsically modulate ipRGC activity, can also affect synaptic inputs to ipRGCs, thereby tuning retina circuits involved in nonimage-forming visual functions.

Enhancing food preservation with postbiotic metabolites γ-aminobutyric acid (GABA) and bacteriocin-like inhibitory substances (BLIS) produced by Lactobacillus brevis C23 co-cultures in plant-based medium.

Lactic acid bacteria (LAB) can produce γ-aminobutyric acid (GABA) with antioxidant properties and sedative effects when it binds to the GABA receptor in the human brain. LAB can also produce bacteriocin-like inhibitory substances (BLIS) with antimicrobial capabilities during carbohydrate fermentation. GABA and BLIS are natural compounds with potential health benefits and food preservation properties. Lactobacillus brevis C23 was co-cultured with three different LABs as inducers, which produced the highest GABA content and BLIS activity. They were cultured in various plant-based media to obtain an edible and better-tasting final product over commercially available media like MRS broth. A coconut-based medium with additives was optimized using response surface methodology (RSM) to increase GABA and BLIS production. The optimized medium for maximum GABA production (3.22 ± 0.01 mg/mL) and BLIS activity (84.40 ± 0.44%) was a 5.5% coconut medium containing 0.23% glucose, 1.44% Tween 20, 0.48% L-glutamic acid, and 0.02% pyridoxine. Due to the presence of GABA, the cell-free supernatant (CFS) as a postbiotic showed higher antioxidant activity than other food preservatives like nisin and potassium sorbate. Finally, microbiological tests on food samples showed that the postbiotic was more effective than other preservatives at combating the growth of LAB, molds and coliform bacteria, making it a possible food preservative.

Mechanism of Salt Tolerance and Plant Growth Promotion in Priestia megaterium ZS-3 Revealed by Cellular Metabolism and Whole-Genome Studies.

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies have shown that Priestia megaterium ZS-3(ZS-3) can effectively help plants tolerate salinity stress. However, how ZS-3 regulates its metabolic adaptations in saline environments remains unclear. In this study, we monitored the metabolic rearrangement of compatibilisers in ZS-3 and combined the findings with genomic data to reveal how ZS-3 survives in stressful environments, induces plant growth, and tolerates stress. The results showed that ZS-3 tolerated salinity levels up to 9%. In addition, glutamate and trehalose help ZS-3 adapt to osmotic stress under low NaCl stress, whereas proline, K+, and extracellular polysaccharides regulate the osmotic responses of ZS-3 exposed to high salt stress. Potting experiments showed that applying the ZS-3 strain in saline and neutral soils could effectively increase the activities of soil acid phosphatase, urease, and invertase in both soils, thus improving soil fertility and promoting plant growth. In addition, strain ZS-3-GFP colonised the rhizosphere and leaves of Cinnamomum camphora well, as confirmed by confocal microscopy and resistance plate count analysis. Genomic studies and in vitro experiments have shown that ZS-3 exhibits a variety of beneficial traits, including plant-promoting, antagonistic, and other related traits (such as resistance to saline and heavy metal stress/tolerance, amino acid synthesis and transport, volatile compound synthesis, micronutrient utilisation, and phytohormone biosynthesis/regulatory potential). The results support that ZS-3 can induce plant tolerance to abiotic stresses. These data provide important clues to further reveal the interactions between plants and microbiomes, as well as the mechanisms by which micro-organisms control plant health.

Evaluating Back-to-Back and Day-to-Day Reproducibility of Cortical GABA+ Measurements Using Proton Magnetic Resonance Spectroscopy (1H MRS).

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy (1H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson's r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC.

Synthesis and Receptor Binding Studies of α5 GABAAR Selective Novel Imidazodiazepines Targeted for Psychiatric and Cognitive Disorders.

GABA mediates inhibitory actions through various GABAA receptor subtypes, including 19 subunits in human GABAAR. Dysregulation of GABAergic neurotransmission is associated with several psychiatric disorders, including depression, anxiety, and schizophrenia. Selective targeting of α2/3 GABAARs can treat mood and anxiety, while α5 GABAA-Rs can treat anxiety, depression, and cognitive performance. GL-II-73 and MP-III-022, α5-positive allosteric modulators have shown promising results in animal models of chronic stress, aging, and cognitive disorders, including MDD, schizophrenia, autism, and Alzheimer's disease. Described in this article is how small changes in the structure of imidazodiazepine substituents can greatly impact the subtype selectivity of benzodiazepine GABAAR. To investigate alternate and potentially more effective therapeutic compounds, modifications were made to the structure of imidazodiazepine 1 to synthesize different amide analogs. The novel ligands were screened at the NIMH PDSP against a panel of 47 receptors, ion channels, including hERG, and transporters to identify on- and off-target interactions. Any ligands with significant inhibition in primary binding were subjected to secondary binding assays to determine their Ki values. The newly synthesized imidazodiazepines were found to have variable affinities for the benzodiazepine site and negligible or no binding to any off-target profile receptors that could cause other physiological problems.

Oral exposure to aluminum chloride for 28 days suppresses neural stem cell proliferation and increases mature granule cells in adult hippocampal neurogenesis of young-adult rats.

Aluminum (Al), a common light metal, affects the developing nervous system. Developmental exposure to Al chloride (AlCl3 ) induces aberrant neurogenesis by targeting neural stem cells (NSCs) and/or neural progenitor cells (NPCs) in the dentate gyrus (DG) of rats and mice. To investigate whether hippocampal neurogenesis is similarly affected by AlCl3 exposure in a general toxicity study, AlCl3 was orally administered to 5-week-old Sprague Dawley rats at dosages of 0, 4000, or 8000 ppm in drinking water for 28 days. AlCl3 downregulated Sox2 transcript level in the DG at the highest dosage and produced a dose-dependent decrease of SOX2+ cells without altering numbers of GFAP+ or TBR2+ cells in the subgranular zone, suggesting that AlCl3 decreases Type 2a NPCs. High-dose exposure downregulated Pcna, upregulated Pvalb, and altered expression of genes suggestive of oxidative stress induction (upregulation of Nos2 and downregulation of antioxidant enzyme genes), indicating suppressed proliferation and differentiation of Type 1 NSCs. AlCl3 doses also increased mature granule cells in the DG. Upregulation of Reln may have contributed to an increase of granule cells to compensate for the decrease of Type 2a NPCs. Moreover, upregulation of Calb2, Gria2, Mapk3, and Tgfb3, as well as increased numbers of activated astrocytes in the DG hilus, may represent ameliorating responses against suppressed neurogenesis. These results suggest that 28-day exposure of young-adult rats to AlCl3 differentially targeted NPCs and mature granule cells in hippocampal neurogenesis, yielding a different pattern of disrupted neurogenesis from developmental exposure.

GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.

Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABAB receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.

Optimization of fermentation for γ-aminobutyric acid (GABA) production by yeast Kluyveromyces marxianus C21 in okara (soybean residue).

γ-Aminobutyric acid (GABA) is a non-protein amino acid with a variety of physiological functions. Recently, yeast Kluyveromyces marxianus strains involved in the catabolism and anabolism of GABA can be used as a microbial platform for GABA production. Okara, rich in nutrients, can be used as a low-cost fermentation substrate for the production of functional materials. This study first proved the advantages of the okara medium to produce GABA by K. marxianus C21 when L-glutamate (L-Glu) or monosodium glutamate (MSG) is the substrate. The highest production of GABA was obtained with 4.31 g/L at optimization condition of culture temperature 35 °C, fermentation time 60 h, and initial pH 4.0. Furthermore, adding peptone significantly increased the GABA production while glucose and vitamin B6 had no positive impact on GABA production. This research provided a powerful new strategy of GABA production by K. marxianus C21 fermentation and is expected to be widely utilized in the functional foods industry to increase GABA content for consumers as a daily supplement as suggested.

Understanding the Molecular Mechanisms of Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD): Towards the Development of SSADH-Targeted Medicine.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare genetic disorder caused by inefficient metabolic breakdown of the major inhibitory neurotransmitter, γ-aminobutyric acid (GABA). Pathologic brain accumulation of GABA and γ-hydroxybutyrate (GHB), a neuroactive by-product of GABA catabolism, leads to a multitude of molecular abnormalities beginning in early life, culminating in multifaceted clinical presentations including delayed psychomotor development, intellectual disability, hypotonia, and ataxia. Paradoxically, over half of patients with SSADHD also develop epilepsy and face a significant risk of sudden unexpected death in epilepsy (SUDEP). Here, we review some of the relevant molecular mechanisms through which impaired synaptic inhibition, astrocytic malfunctions and myelin defects might contribute to the complex SSADHD phenotype. We also discuss the gaps in knowledge that need to be addressed for the implementation of successful gene and enzyme replacement SSADHD therapies. We conclude with a description of a novel SSADHD mouse model that enables 'on-demand' SSADH restoration, allowing proof-of-concept studies to fine-tune SSADH restoration in preparation for eventual human trials.

Influence of fresh-cut process on γ-aminobutyric acid (GABA) metabolism and sensory properties in carrot.

Effect of fresh-cut procedure on the accumulation of GABA in carrots via γ-aminobutyric acid (GABA) shunt and polyamines degradation pathway was investigated. Results showed that fresh-cut processing enhanced glutamate decarboxylase (GAD) activity and expression levels of DcGAD1 and DcGAD2, while reduced GABA transaminase (GABA-T) activity and DcGABA-T1 expression level, which induced the more glutamate (Glu) conversion to GABA. Polyamines (PAs) in shredded carrots were significantly lower than the whole, due to the elevated activities of diamine oxidase (DAO), polyamine oxidase (PAO) and aminoaldehyde dehydrogenase (AMADH) and DcPAO expression level, which indicated that the polyamines degradation pathway was activated and more PAs were converted to GABA. These results suggested that fresh-cut procedure can induce the accumulation of GABA through activating GABA shunt and polyamines degradation pathway. Besides, fresh-cut processing treatment did not have much adverse effect on the organoleptic quality of carrots. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at (10.1007/s13197-021-05039-y).

Photoaffinity labeling identifies an intersubunit steroid-binding site in heteromeric GABA type A (GABAA) receptors.

Allopregnanolone (3α5α-P), pregnanolone, and their synthetic derivatives are potent positive allosteric modulators (PAMs) of GABAA receptors (GABAARs) with in vivo anesthetic, anxiolytic, and anti-convulsant effects. Mutational analysis, photoaffinity labeling, and structural studies have provided evidence for intersubunit and intrasubunit steroid-binding sites in the GABAAR transmembrane domain, but revealed only little definition of their binding properties. Here, we identified steroid-binding sites in purified human α1ß3 and α1ß3γ2 GABAARs by photoaffinity labeling with [3H]21-[4-(3-(trifluoromethyl)-3H-diazirine-3-yl)benzoxy]allopregnanolone ([3H]21-pTFDBzox-AP), a potent GABAAR PAM. Protein microsequencing established 3α5α-P inhibitable photolabeling of amino acids near the cytoplasmic end of the ß subunit M4 (ß3Pro-415, ß3Leu-417, and ß3Thr-418) and M3 (ß3Arg-309) helices located at the base of a pocket in the ß+-α- subunit interface that extends to the level of αGln-242, a steroid sensitivity determinant in the αM1 helix. Competition photolabeling established that this site binds with high affinity a structurally diverse group of 3α-OH steroids that act as anesthetics, anti-epileptics, and anti-depressants. The presence of a 3α-OH was crucial: 3-acetylated, 3-deoxy, and 3-oxo analogs of 3α5α-P, as well as 3ß-OH analogs that are GABAAR antagonists, bound with at least 1000-fold lower affinity than 3α5α-P. Similarly, for GABAAR PAMs with the C-20 carbonyl of 3α5α-P or pregnanolone reduced to a hydroxyl, binding affinity is reduced by 1,000-fold, whereas binding is retained after deoxygenation at the C-20 position. These results provide a first insight into the structure-activity relationship at the GABAAR ß+-α- subunit interface steroid-binding site and identify several steroid PAMs that act via other sites.

Use of Both Fluoro-Jade B and Hematoxylin and Eosin to Detect Cell Death in the Juvenile Rat Brain Exposed to NMDA-Receptor Antagonists or GABA-Receptor Agonists in Safety Assessment.

Administration of pediatric anesthetics with N-methyl D-aspartate (NMDA)-receptor antagonist and/or γ-aminobutyric acid (GABA) agonist activities may result in neuronal degeneration and/or neuronal cell death in neonatal rats. Evaluating pediatric drug candidates for this potential neurotoxicity is often part of overall preclinical new drug development strategy. This specialized assessment may require dosing neonatal rats at postnatal day 7 at the peak of the brain growth spurt and evaluating brain tissue 24 to 48 hours following dosing. The need to identify methods to aid in the accurate and reproducible detection of lesions associated with this type of neurotoxic profile is paramount for meeting the changing needs of neuropathology assessment and addressing emerging challenges in the neuroscience field. We document the use of Fluoro-Jade B (FJB) staining, to be used in conjunction with standard hematoxylin and eosin staining, to detect acute neurodegeneration and neuronal cell death that can be caused by some NMDA-receptor antagonists and/or GABA agonists in the neonatal rat brain. The FJB staining is simple, specific, and sensitive and can be performed on brain specimens from the same cohort of animals utilized for standard neurotoxicity assessment, thus satisfying animal welfare recommendations with no effect on achievement of scientific and regulatory goals.

Glutamine + glutamate level predicts the magnitude of microstructural organization in the gray matter in the healthy elderly.

BACKGROUND: Diffusion tensor imaging (DTI), which is a technique for measuring the degree and direction of movement of water molecules in tissue, has been widely used to noninvasively assess white matter (WM) or gray matter (GM) microstructures in vivo. Mean diffusivity (MD), which is the average diffusion across all directions, has been considered as a marker of WM tract degeneration or extracellular space enlargement in GM. Recent lines of evidence suggest that cortical MD can better identify early-stage Alzheimer's disease than structural morphometric parameters in magnetic resonance imaging. However, knowledge of the relationships between cortical MD and other biological factors in the same cortical region, e.g. metabolites, is still limited. METHODS: Thirty-three healthy elderly individuals [aged 50-77 years (mean, 63.8±7.4 years); 11 males and 22 females] were enrolled. We estimated the associations between cortical MD and neurotransmitter levels. Specifically, we measured levels of γ-aminobutyric acid (GABA) and glutamate + glutamine (Glx), which are inhibitory and excitatory neurotransmitters, respectively, in medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) using MEGA-PRESS magnetic resonance spectroscopy, and we measured regional cortical MD using DTI. RESULTS: Cortical MD was significantly negatively associated with Glx levels in both mPFC and PCC. No significant association was observed between cortical MD and GABA levels in either GM region. CONCLUSION: Our findings suggest that degeneration of microstructural organization in GM, as determined on the basis of cortical MD measured by DTI, is accompanied by the decline of Glx metabolism within the same GM region.

Probiotic potential of γ-aminobutyric acid (GABA)-producing yeast and its influence on the quality of cheese.

Kazakh cheese is a traditional dairy product in Xinjiang, China. To study the function and potential probiotic characteristics of yeast in Kazakh cheese and its contribution to cheese fermentation, we screened the γ-aminobutyric acid (GABA)-producing yeasts Pichia kudriavzevii 1-21, Kluyveromyces marxianus B13-5, Saccharomyces cerevisiae DL6-20, and Kluyveromyces lactis DY1-10. We investigated the potential probiotic properties of these strains and their use in cheese fermentation (cheeses designated CSP, CSM, CSS, and CSI, respectively); a control with no added yeast was designated CS. The results showed that the 4 yeast strains all showed high self-polymerization (2- and 24-h autoaggregation capacity of >80 and 90%, respectively), hydrophobicity (40-92% variation, low hydrophobicity in xylene, but within the range of probiotics), and the ability to survive the gastrointestinal tract (survival rate >75% after simulation), indicating the probiotic ability of the strains in vitro. The GABA production capacity of the CSM cheese increased (to 95.6 mg/100 g), but its protein content did not change significantly, and amino acid degradation was obvious. The GABA production capacity of the CSS cheese decreased (to 450 mg/kg); its protein content declined, and its amino acid content increased. Except for water and protein, we found no obvious differences in most physical and chemical indicators. Kluyveromyces marxianus B13-5 helped to form the desired texture. Multivariate statistical analysis showed that fermentation of the cheese with the 4 yeasts improved the production of esters and alcohols. The CSS cheese had good aroma production performance, because S. cerevisiae DL6-20 produced high concentrations of isoamyl alcohol, hexanoic acid ethyl ester, benzyl alcohol, octanoic acid ethyl ester, 3-hydroxy-2-butanone, and hexanoic acid; the content of 2-methyl-propanoic acid was low. Compared with the CSP cheese, the CSI and CSM cheeses had a fruitier aroma and a milder odor, but the CSI and CSM cheeses had high concentrations of ethyl acetate, butanoic acid, ethyl ester, 3-methyl-1-butanol-acetate, ethyl hexanoate, ethyl octanoate, acetic acid 2-phenylethyl ester, and ethyl lactate; concentrations of 3-methyl-butanoic acid, propanoic acid, acetic acid, and butanoic acid were low. The CSP cheese had stronger acid-producing ability. The order of fragrance production performance was CSS > CSI, CSM > CSP > CS. Research into the fermentation mechanisms of GABA-producing yeast in cheese will provide a theoretical basis for the quality control and industrial production of Kazakh cheese.

Effect of adzuki bean sprout fermented milk enriched in γ-aminobutyric acid on mild depression in a mouse model.

This study focused on the ability of adzuki bean (Vigna angularis) sprout fermented milk, which is rich in γ-aminobutyric acid (GABA), to relieve anxiety and mild depression. A high-yield GABA-producing strain, Lactobacillus brevis J1, from a healthy cow was screened, and its physiological and probiotic properties were evaluated. The effect of adzuki bean sprout fermented milk was investigated in vivo in a chronic depression mouse model. The results showed that Lb. brevis J1 had excellent probiotic properties, grew well at low pH and 3% NaCl, and adhered to the surface of HT-29 cells. The GABA-enriched (241.30 ± 1.62 µg/mL) adzuki bean sprout fermented milk prepared with Streptococcus thermophilus, Lactobacillus bulgaricus, and Lactobacillus plantarum, and Lb. brevis J1 can reduce and possibly prevent mild depression-like symptoms in mice (C57/B6) by increasing social interaction and enhancing the pleasure derived from movement. The research revealed that the GABAB-cyclic AMP-protein kinase A-cAMP-response element binding protein (GABAB-cAMP-PKA-CREB) signaling pathway was related to the depression-like symptoms and that levels of 5-hydroxytryptamine, norepinephrine, and dopamine in the hippocampus of mice increased after treatment with the adzuki bean sprout fermented milk. Our results suggest that GABA-enriched dairy products have the potential to prevent or treat mild depression-like symptoms in mice, which suggests a new approach for a dietary therapy to treat chronic social stress.

Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation.

Glaucoma is a leading cause of irreversible blindness worldwide, and increased intraocular pressure (IOP) is a major risk factor. We aimed to determine if early functional and molecular differences in the glaucomatous retina manifest before significant retinal ganglion cell (RGC) loss is apparent. Adenoviral vectors expressing a pathogenic form of myocilin (Ad5.MYOC) were used to induce IOP elevation in C57BL/6 mice. IOP and pattern electroretinograms (pERG) were recorded, and retinas were prepared for RNA sequencing, immunohistochemistry, or to determine RGC loss. Ocular injection of Ad5.MYOC leads to reliable IOP elevation, resulting in significant loss of RGC after nine weeks. A significant decrease in the pERG amplitude was evident in eyes three weeks after IOP elevation. Retinal gene expression analysis revealed increased expression for 291 genes related to complement cascade, inflammation, and antigen presentation in hypertensive eyes. Decreased expression was found for 378 genes associated with the γ-aminobutyric acid (GABA)ergic and glutamatergic systems and axon guidance. These data suggest that early functional changes in RGC might be due to reduced GABAA receptor signaling and neuroinflammation that precedes RGC loss in this glaucoma model. These initial changes may offer new targets for early detection of glaucoma and the development of new interventions.

The Role of Phospholipase C in GABAergic Inhibition and Its Relevance to Epilepsy.

Epilepsy is characterized by recurrent seizures due to abnormal hyperexcitation of neurons. Recent studies have suggested that the imbalance of excitation and inhibition (E/I) in the central nervous system is closely implicated in the etiology of epilepsy. In the brain, GABA is a major inhibitory neurotransmitter and plays a pivotal role in maintaining E/I balance. As such, altered GABAergic inhibition can lead to severe E/I imbalance, consequently resulting in excessive and hypersynchronous neuronal activity as in epilepsy. Phospholipase C (PLC) is a key enzyme in the intracellular signaling pathway and regulates various neuronal functions including neuronal development, synaptic transmission, and plasticity in the brain. Accumulating evidence suggests that neuronal PLC is critically involved in multiple aspects of GABAergic functions. Therefore, a better understanding of mechanisms by which neuronal PLC regulates GABAergic inhibition is necessary for revealing an unrecognized linkage between PLC and epilepsy and developing more effective treatments for epilepsy. Here we review the function of PLC in GABAergic inhibition in the brain and discuss a pathophysiological relationship between PLC and epilepsy.

Role of Receptors in Relation to Plaques and Tangles in Alzheimer's Disease Pathology.

Despite the identification of Aß plaques and NFTs as biomarkers for Alzheimer's disease (AD) pathology, therapeutic interventions remain elusive, with neither an absolute prophylactic nor a curative medication available to impede the progression of AD presently available. Current approaches focus on symptomatic treatments to maintain AD patients' mental stability and behavioral symptoms by decreasing neuronal degeneration; however, the complexity of AD pathology requires a wide range of therapeutic approaches for both preventive and curative treatments. In this regard, this review summarizes the role of receptors as a potential target for treating AD and focuses on the path of major receptors which are responsible for AD progression. This review gives an overall idea centering on major receptors, their agonist and antagonist and future prospects of viral mimicry in AD pathology. This article aims to provide researchers and developers a comprehensive idea about the different receptors involved in AD pathogenesis that may lead to finding a new therapeutic strategy to treat AD.

Low-Dose Ozone Therapy Improves Sleep Quality in Patients with Insomnia and Coronary Heart Disease by Elevating Serum BDNF and GABA.

We studied the effects of low-dose ozone therapy on the sleep quality of patients with coronary heart disease (CHD) and insomnia by measuring the levels of brain-derived neurotrophic factor (BDNF) and GABA in blood serum. The 3-month course of low-dose ozone therapy significantly elevated serum BDNF and GABA in CHD patients with insomnia and improved parameters of anxiety, depression, and sleep quality according to Hospital Anxiety and Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), and Self-Rating Scale of Sleep (SRSS). Ozone therapy also significantly (p<0.05) improved the total antioxidant status of the body by elevating catalase activity and reducing malondialdehyde and 8-OHdeoxyguanosine in the saliva. The serum levels of BDNF and GABA negatively and closely correlated with PSQI and HADS scores. Low-dose ozone therapy improved sleep quality and reduced PSQI and HADS scores due to up-regulation of BDNF and GABA.