Elevated GABA Levels Research Articles

A Review on Phytochemical Constituents Used as Current Treatment Strategies for Neurodegenerative Disease.

In today's time, a diversity of neurodegenerative diseases that widely affect the CNS causing insufficiency in particular brain processes such as memory, mobility, and cognition due to the moderate loss of CNS neurons. This review emphasizes different phytochemical constituents used widely for the prevention or treatment of various neurodegenerative diseases such as Alzheimer's disease (AD) and Parkin-son's disease (PD). Berberin (BBR), which is an isoquinoline class of alkaloid and isolated from the plant Hydrastis condenses and Berberis aaristata, has both acetylcholine esterase (AChE) inhibiting properties as well as monoamine oxidase (MAO) inhibiting properties involved in the betterment of AD by decreasing the production of reactive oxygen species (ROS). Like BBR, Physostigmine, isolated from the Physostigma venenosum / Calabar bean and belongs to the family Leguminosae, and Morphine, isolated from the plant Papaver somniferum / Opium poppy or Breadseed poppy, also has a significant impact on the management and treatment of AD and PD by reducing both neuroinflammation and pro-inflammatory cytokines production. Morphine bineurodegenerative diseases with μ-opioid receptor (MOR) in CNS elevate GABA levels in the synaptic cleft of the brain and reduces the neurotoxicity via stimulation of MOR. It has been discovered that physostigmine improves cognitive function in AD patients and reduces α-synu-clein expression in PD neural cell lines. Isorhyncophylline (IRN) is a Chinese herbal medicine isolated from the plant Uncaria rhyncophylla which provides neuroprotective efficiency against neurotoxicity that occurs by amyloid β (the main component of amyloid plaques) found in the brain of people with AD.

Sub-acute Inhalation Exposure to Aluminum Oxide Nanoparticles and its Effects on Wistar Rats as Opposed to the Micro-sized Chemical Analog.

Aluminum oxide nanoparticles (Al2O3 NPs) are widely used in various productions. Simultaneously, many research works report the toxic effects of this nanomaterial. Given that, there is a growing risk of negative effects produced by Al2O3 NPs on public health. This study aims to investigate the toxic effects of Al2O3 NPs as opposed to the micro-sized chemical analogue under sub-acute inhalation exposure. We identified the physical properties of Al2O3 NPs as opposed to the micro- sized chemical analogue, including size, specific surface area, and total pore volume. Inhalation exposure to Al2O3 NPs was simulated on Wistar rats in a chamber for whole-body. The animals were exposed for 4 hours each day for 28 days. NPs and MPs concentrations in the chamber were kept at ~ 1/4000 from LC50. Rats' behavior was examined prior to the exposure period and after it; after the last daily exposure, we examined biochemical and hematological blood indicators, NPs and MPs bioaccumulation, and pathomorphological changes in organ tissues. The tested Al2O3 sample is a nanomaterial according to its analyzed physical properties. Rats' behavior changed more apparently under exposure to NPs compared to MPs. Aluminum levels, which were 1.62-55.20 times higher than the control, were identified in the lungs, liver, brain, and blood under exposure to NPs. These levels were also 1.55-7.65 times higher than the control under exposure to MPs. Biochemical indicators of rats' blood also changed under exposure to NPs against the control. We identified more active ALT, AST, ALP, and LDH, elevated levels of GABA, MDA, and conjugated bilirubin, and a lower level of Glu. As opposed to exposure to MPs, ALT, AST, and ALP were more active; GABA and MDA levels were higher; Glu level was lower. Under exposure to NPs, the number of platelets grew, whereas no similar effect occurred under exposure to MPs. We established pathomorphological changes in tissues of the lungs, brain, heart, and liver under exposure to Al2O3 NPs; similar changes occurred only in the lungs under exposure to MPs. Exposure to NPs induced changes in tissue structures in a wider range of various organs, and these changes were more apparent than under exposure to MPs. Greater toxicity of Al2O3 NPs as opposed to MPs is evidenced by a wider range of organs where their bioaccumulation occurs, more apparent pathomorphological and pathological functional changes. Established peculiarities of toxic effects produced by the analyzed nanomaterial should be considered when developing hygienic recommendations aimed at preventing and mitigating adverse impacts of Al2O3 NPs on human health under inhalation exposure.

Sustained Inhibition of GABA-AT by OV329 Enhances Neuronal Inhibition and Prevents Development of Benzodiazepine Refractory Seizures.

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain which mediates its rapid effects on neuronal excitability via ionotropic GABAA receptors. GABA levels in the brain are critically dependent upon GABA-aminotransferase (GABA-AT) which promotes its degradation. Vigabatrin, a low-affinity GABA-AT inhibitor, exhibits anticonvulsant efficacy, but its use is limited due to cumulative ocular toxicity. OV329 is a rationally designed, next-generation GABA-AT inhibitor with enhanced potency. We demonstrate that sustained exposure to OV329 in mice reduces GABA-AT activity and subsequently elevates GABA levels in the brain. Parallel increases in the efficacy of GABAergic inhibition were evident, together with elevations in electroencephalographic delta power. Consistent with this, OV329 exposure reduced the severity of status epilepticus and the development of benzodiazepine refractory seizures. Thus, OV329 may be of utility in treating seizure disorders and associated pathologies that result from neuronal hyperexcitability.

GABAergic Dysregulation in Autism Spectrum Disorder: Collaborative Insights on Neurobiological Complexity

This paper synthesizes insights from two collaborative studies investigating GABAergic dysregulation in autism spectrum disorder (ASD). The study by Al-Otaish et al. (2018) explored amino acid profiles in 40 male children with ASD, revealing elevated GABA levels and altered glutamate/glutamine ratios. In parallel, El-Ansary et al. (2021) focused on GABAergic dysfunction and apoptotic markers in a cohort of 20 ASD children. Both studies underscored GABA's pivotal role in ASD neurobiology, emphasizing its potential as a diagnostic biomarker. ASD, characterized by intricate genetic, environmental, and neurobiological factors, exhibits a heterogeneous landscape. The reduction in plasma GABA levels, concurrent with heightened apoptotic markers, implicates GABAergic dysregulation in synaptic pathologies, offering novel insights into the disorder's complexity. Despite methodological limitations and modest sample sizes, these findings contribute significantly to understanding GABAergic function in ASD. Future research should prioritize larger cohorts, diverse demographics, and refined methodologies to enhance generalizability. Integrating GABAergic insights into a broader neurobiological framework, the precision medicine approach holds promise for personalized interventions. This collaborative effort advances the comprehension of GABAergic dysregulation in ASD, contributing to a mosaic of knowledge vital for navigating this heterogeneous neurodevelopmental disorder.

Finding the optimal light quality and intensity for the withering process of fuding Dabai tea and its impact on quality formation

This study investigates the pivotal role of withering in shaping the quality of white tea. We used a single-factor experimental design to optimize both the light quality and intensity during the withering process. Using gas chromatography-mass spectrometry (GC-MS), sensory evaluation, and physical and chemical analyses, we identified the ideal parameters as yellow light at an intensity of 5000 lx. Subsequently, we used non-targeted metabolomics and transcriptomics to analyze the mechanism of white tea quality formation at various stages of withering. The results showed significant changes to flavonoids during the withering process, with heightened F3′5′H (flavonoid3,5-hydroxylase) gene expression leading to increased levels of quercetin, myricetin, and luteolin. Conversely, the decreased catechin content was attributed to the decreased expression of most genes in the catechin synthesis pathway. The elevated levels of leucine, isoleucine, and GABA in free amino acids were due to a significant increase in the expression of the genes that synthesize them. Hormone and WGCNA analyses substantiated the importance of ABA, JA, and other key genes in shaping white tea quality during withering. These combined factors orchestrate the gradual formation of the distinctive characteristics of high-quality white tea.

Peculiarities of toxic effects produced by aluminum oxide nano- and microparticles under multiple inhalation exposure

Introduction. Aluminum oxide nanoparticles (Al2O3 NPs) are widely used in nanotechnologies employed in various branches including chemical, food, and medical industry and perfume and cosmetics production. This high demand for Al2O3 NPs, given the wide-scale development of nanoindustries, can, in its turn, lead to ambient air pollution that creates public health risks under long-term exposure to it. Given that, it seems relevant to perform profound investigation with its focus on pathogenetic features of toxic effects produced by these nanoparticles and comparatively analyze them with effects produced by a micro-sized chemical analog under inhalation exposure to introduce more effective prevention.
 Materials and methods. We examined chemical properties of Al2O3, nano- and microparticles (MPs) in an experiment on Wistar rats, comparatively analyzed the results and described pathogenetic features of toxic effects produced by the examined particles under multiple inhalation exposure. 
 Results. The examined samples were a nanomaterial judging by such parameters as particle size, shape, surface area, and total pore volume. They differed substantially from their micro-sized analog. Exposure to Al2O3 NPs causes more pronounced changes in the behaviour of rats relative to MPs. Under exposure to Al2O3 NPs, aluminum concentrations were statistically significantly by 1.62–55.2 times higher in the lungs, liver, brain and blood. The concentration of the examined elements was by 1.55–7.65 times higher in these organs as compared to exposure to the micro-sized particles. Exposure to Al2O3 NPs induced changes in biochemical indicators of negative effects against the control (exposure to micro-sized particles). We established higher activity of ALT, AST, AP, LDH, and elevated levels of direct bilirubin, GABA, glutamine acid, and MDA against the same indicators in the control group. Pathomorphological changes were identified in the lungs, brain, heart, and liver under exposure to Al2O3 NPs whereas exposure to the micro-sized analog induced such changes only in the lungs. Exposure to NPs induced more apparent changes in tissue structures in many organs. 
 Limitations. The study involved only multiple inhalation exposure to Al2O3 NPs and MPs in an experiment on Wistar rats.
 Conclusion. Al2O3 NPs are more toxic than their micro-sized chemical analog; this is evidenced by a greater number of organs where bioaccumulation occurs, more apparent pathomorphological changes and pathological functional disorders. The study results should be considered when developing hygienic recommendations aimed at preventing and minimizing negative effects produced by Al2O3 NPs on human health.

Measurement of neuro-energetics and neurotransmission in the rat olfactory bulb using 1H and 1H-[13C] NMR spectroscopy.

The olfactory bulb (OB) plays a fundamental role in the sense of smell and has been implicated in several pathologies, including Alzheimer's disease. Despite its importance, high metabolic activity and unique laminar architecture, the OB is not frequently studied using MRS methods, likely due to the small size and challenging location. Here we present a detailed metabolic characterization of OB metabolism, in terms of both static metabolite concentrations using 1H MRS and metabolic fluxes associated with neuro-energetics and neurotransmission by tracing the dynamic 13C flow from intravenously administered [1,6-13C2]-glucose, [2-13C]-glucose and [2-13C]-acetate to downstream metabolites, including [4-13C]-glutamate, [4-13C]-glutamine and [2-13C]-GABA. The unique laminar architecture and associated metabolism of the OB, distinctly different from that of the cerebral cortex, is characterized by elevated GABA and glutamine levels, as well as increased GABAergic and astroglial energy metabolism and neurotransmission. The results show that, despite the technical challenges, high-quality 1H and 1H-[13C] MR spectra can be obtained from the rat OB in vivo. The derived metabolite concentrations and metabolic rates demonstrate a unique metabolic profile for the OB. The metabolic model provides a solid basis for future OB studies on functional activation or pathological conditions.

Neuroprotective and detrimental effects of astrocytes on amyloid plaque formation

In Alzheimer’s disease (AD) brains, reactive astrocytes and microglia are frequently seen around amyloid plaques. The functions of microglia have been extensively studied, such as the neuroprotective barrier they form to prevent plaque growth and their release of inflammatory cytokines. However, the functions of astrocytes are less well known. Here I review the ongoing research on astrocytic functions around plaques. Recent studies suggest that astrocytes play an important role in downregulating Aβ production through the production of cholesterol and reducing plaque deposition through Aβ uptake and clearance. Astrocytes also interact with microglia through the clusterin and C3 pathways, possibly altering Aβ fibril formation and microglia phagocytosis. On the other hand, astrocytes contribute to elevated glutamate and GABA levels, potentially causing excitotoxicity and accelerating cognitive decline. Finally, I review two possible therapeutic treatments, ceftriaxone and selegiline, for alleviating AD pathology by targeting astrocyte functions. Given their crucial and complex roles in AD, a better understand of astrocyte functions would contribute to a greater understanding of AD progression and uncover new therapeutic targets.

Structural basis of GABA reuptake inhibition.

γ-Aminobutyric acid (GABA) transporter 1 (GAT1), a member of the neurotransmitter sodium symporter (NSS) family, regulates neuronal excitation by clearing the synaptic cleft of the main inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating GABA levels in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy. Here we present the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor, the anticonvulsant tiagabine. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine. Tiagabine's pharmacodynamic profile, confirmed by our experimental data, suggests initial binding to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step induced-fit mechanism of inhibition. The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators.

Elevation of GABA levels in the globus pallidus disinhibits the thalamic reticular nucleus and desynchronized cortical beta oscillations

The external globus pallidus (GP) is a GABAergic node involved in motor control regulation and coordinates firing and synchronization in the basal ganglia–thalamic–cortical network through inputs and electrical activity. In Parkinson's disease, high GABA levels alter electrical activity in the GP and contribute to motor symptoms. Under normal conditions, GABA levels are regulated by GABA transporters (GATs). GAT type 1 (GAT-1) is highly expressed in the GP, and pharmacological blockade of GAT-1 increases the duration of currents mediated by GABA A receptors and induces tonic inhibition. The functional contribution of the pathway between the GP and the reticular thalamic nucleus (RTn) is unknown. This pathway is important since the RTn controls the flow of information between the thalamus and cortex, suggesting that it contributes to cortical dynamics. In this work, we investigated the effect of increased GABA levels on electrical activity in the RTn by obtaining single-unit extracellular recordings from anesthetized rats and on the motor cortex (MCx) by corticography. Our results show that high GABA levels increase the spontaneous activity rate of RTn neurons and desynchronize oscillations in the beta frequency band in the MCx. Our findings provide evidence that the GP exerts tonic control over RTn activity through the GP–reticular pathway and functionally contributes to cortical oscillation dynamics.

The Ameliorative Effect of Empagliflozin in Vigabatrin-Induced Cerebellar/Neurobehavioral Deficits: Targeting mTOR/AMPK/SIRT-1 Signaling Pathways

Introduction. Vigabatrin (VGB) is an antiepileptic drug that acts to irreversibly inhibit the γ-aminobutyric acid (GABA) transaminase enzyme, elevating GABA levels. Broad studies have established that long-term treatment and/or high doses of VGB lead to variable visual defects. However, little attention has been paid to its other side effects, especially those demonstrating cerebellar involvement. Sodium glucose-linked co-transporter 2 (SGLT2) inhibitors are antidiabetic agents with protective effects far greater than expected based on their anti-hyperglycemic effect. Method. Our study herein was designed to investigate the possible ameliorative effect of empagliflozin, the SGLT2 inhibitors, in VGB-induced cerebellar toxicity. A total of 40 male Wistar rats were allocated equally into 4 groups: Group I: control group; Group II: VGB group; Group III empagliflozin treated VGB group; and Group IV: empagliflozin treated group. All groups were subjected to the detection of cerebellar messenger RNA gene expression of silent mating type information regulation 2 homolog 1 (SIRT1) and Nucleoporin p62 (P62). Mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase (AMPK), and beclin1 levels were assessed by the ELISA technique while malondialdehyde (MDA) level and superoxide dismutase (SOD) activity were detected spectrophotometrically. Immuno-histochemical studies, focusing on glial fibrillary acidic protein (GFAP) and S100 were performed, and the optical color density and the mean area percentage of GFAP positive astrocytes and the number of S 100 positive cells were also counted. Results. Following empagliflozin treatment, we documented significant upregulation of both SIRT1 and P62 mRNA gene expression. Additionally, AMPK, Beclin1 levels, and SOD activity were significantly improved, while both mTOR and MDA levels were significantly reduced. Conclusions. We concluded for the first time that empagliflozin efficiently ameliorated the VGB-induced disrupted mTOR/AMPK/SIRT-1 signaling axis with subsequent improvement of the autophagy machinery and mitigation of the oxidative and inflammatory cellular environment, paving the way for an innovative therapeutic potential in managing VGB-induced neurotoxicity.

Effects of sex hormones on brain GABA and glutamate levels in a cis- and transgender cohort

Sex hormones affect the GABAergic and glutamatergic neurotransmitter system as demonstrated in animal studies. However, human research has mostly been correlational in nature. Here, we aimed at substantiating causal interpretations of the interaction between sex hormones and neurotransmitter function by using magnetic resonance spectroscopy imaging (MRSI) to study the effect of gender-affirming hormone treatment (GHT) in transgender individuals.Fifteen trans men (TM) with a DSM-5 diagnosis of gender dysphoria, undergoing GHT, and 15 age-matched cisgender women (CW), receiving no therapy, underwent MRSI before and after at least 12 weeks. Additionally, sex differences in neurotransmitter levels were evaluated in an independent sample of 80 cisgender men and 79 cisgender women. Mean GABA+ (combination of GABA and macromolecules) and Glx (combination of glutamate and glutamine) ratios to total creatine (GABA+/tCr, Glx/tCr) were calculated in five predefined regions-of-interest (hippocampus, insula, pallidum, putamen and thalamus).Linear mixed models analysis revealed a significant measurement by gender identity effect (pcorr. = 0.048) for GABA+/tCr ratios in the hippocampus, with the TM cohort showing decreased GABA+/tCr levels after GHT compared to CW. Moreover, analysis of covariance showed a significant sex difference in insula GABA+/tCr ratios (pcorr. = 0.049), indicating elevated GABA levels in cisgender women compared to cisgender men.Our study demonstrates GHT treatment-induced GABA+/tCr reductions in the hippocampus, indicating hormone receptor activation on GABAergic cells and testosterone-induced neuroplastic processes within the hippocampus. Moreover, elevated GABA levels in the female compared to the male insula highlight the importance of including sex as factor in future MRS studies. Data availability statementDue to data protection laws processed data is available from the authors upon reasonable request. Please contact rupert.lanzenberger@meduniwien.ac.at with any questions or requests.

Putaminal y-Aminobutyric Acid Modulates Motor Response to Dopaminergic Therapy in Parkinson's Disease.

Motor response to dopaminergic therapy is a characteristic of patients with Parkinson's disease (PD). Whether nondopaminergic neurotransmitters contribute to treatment response is uncertain. The aim of this study is to determine whether putaminal y-aminobutyric acid (GABA) levels are associated with dopaminergic motor response. We assessed putaminal GABA levels in 19 PD patients and 13 healthy controls (HCs) utilizing ultra-high field proton magnetic resonance spectroscopy. Motor performance was evaluated using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale, Part III, in the ON and OFF states. Statistical analysis comprised group comparisons, correlation analysis, and multiple linear regression. In PD, GABA levels were significantly higher compared to HCs (1.50 ± 0.26 mM vs. 1.26 ± 0.31 mM, P= 0.022). Furthermore, GABA levels were independent predictors of absolute and relative dopaminergic treatment response. Our findings indicate that elevated putaminal GABA levels are associated with worse dopaminergic response in PD, emphasizing the essential role of nondopaminergic neurotransmitters in motor response. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Elevated GABA levels in the medial prefrontal cortex and lower estrogen levels abolish cocaine sensitization behavior in ovariectomized female rats

Animal models show that cocaine sensitization, a behavioral marker of addiction, is more significant in intact gonadal female than male rats and ovariectomy suppress this behavior in female rats. However, few studies explore changes in neurotransmission related to this phenomenon. Here we investigated the in vivo changes on GABA, glutamate, and taurine levels in the medial prefrontal cortex (mPFC) of gonadal intact or ovariectomized female rats after a cocaine challenge administration. Adult female rats were bilaterally ovariectomized (OVX), or sham-operated (SHAM) and randomly assigned to control (CTR), acute (ACT), or repeated (RPT) cocaine administration groups. In the challenge day, after eight days of daily cocaine (15 mg/kg) or saline administration and ten days of washout and stereotaxic surgery, RPT and ACT groups received cocaine, and the CTR group received saline. Horizontal locomotion was monitored concomitantly with microdialysate collection to determine extracellular GABA, glutamate, and taurine levels. Hormonal determination in blood samples confirmed the lower hormonal status of the OVX. Cocaine sensitization occurred in SHAM-RPT female rats after the challenge administration. Non-sensitized OVX-RPT rats showed a peak of GABA at 30 min after cocaine administration, with no change on glutamate and taurine levels. Therefore, elevated GABA levels in the mPFC and lower serum estrogen levels abolish cocaine sensitization behavior in ovariectomized female rats. We discuss some possible implications of these finding for future models of cocaine sensitization research lighting in the female hormonal influence.

Increased GABAergic development in iPSC-derived neurons from patients with sporadic Alzheimer’s disease

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, and the underlying molecular mechanisms of this neurodegenerative disorder are still unclear. γ-Aminobutyric acid (GABA) neurons play an essential role in the excitatory/inhibitory (E/I) balance in the brain, and the GABAergic system may contribute to the pathogenesis of AD. We used human induced pluripotent stem cells (iPSCs) generated from sporadic AD (SAD) patients to analyze the phenotype and transcriptional profiles of SAD iPSC-derived neural cells. We observed reduced neurogenesis and increased astrogenesis in SAD neural differentiation. We discovered elevated levels of GABA, glutamate decarboxylase 67 (GAD67), and vesicular GABA transporter (vGAT) in SAD neurons that indicated increased GABAergic development. Gene expression profiling of SAD neural cultures showed upregulation of the GABAergic signaling pathway and downregulation of the neurogenesis pathway. We presumed that the GABAergic transmission system might be enhanced in SAD neurons, as an early pathological change of SAD, which provides a novel target and new direction for the development of more effective therapeutic strategies.

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam.

Epilepsy is often treated with a combination of antiepileptic drugs. Although neurosteroids are potent anticonvulsants, little is known about their combination potential for the treatment of refractory epilepsy. Here, we investigated the combination efficacy of neurosteroids allopregnanolone (AP, brexanolone) and ganaxolone (GX) with the GABA-reuptake inhibitor tiagabine (TG) or the benzodiazepine midazolam (MDZ) on tonic inhibition in dentate gyrus granule cells and seizure protection in the hippocampus kindling and 6-Hz seizure models. Isobolographic analysis indicated that combinations of GX and TG or AP and TG at three standard ratios (1:1, 3:1, and 1:3) displayed significant synergism in augmenting tonic inhibition. In pharmacological studies, GX, AP, and TG produced dose-dependent antiseizure effects in mice (ED50 = 1.46, 4.20, and 0.20 mg/kg, respectively). The combination of GX and TG at the fixed ratio of 1:1 exerted the greatest combination index (CI = 0.53), indicating strong synergistic interaction in seizure protection. In addition, combination regimens of AP and TG showed robust synergism for seizure protection (CI = 0.4). Finally, combination regimens of GX and MDZ elicited synergistic (CI = 0.6) responses for seizure protection. These results demonstrate striking synergism of neurosteroids and TG combination for seizure protection, likely because of their effects at extrasynaptic GABA type A (GABA-A) receptors from TG-induced elevation in GABA levels. Superadditive antiseizure activity of neurosteroid-MDZ combinations may stem from their actions at both synaptic and extrasynaptic GABA-A receptors. Together, these findings provide a potential mechanistic basis for combination potential of neurosteroids with TG or benzodiazepines for the management of refractory epilepsy, status epilepticus, and seizure disorders. SIGNIFICANCE STATEMENT: This paper investigates for the first time the potential synergistic interactions between two neurosteroids with anticonvulsant properties, allopregnanolone (brexanolone) and the very similar synthetic analog, ganaxolone, and two conventional antiepileptic drugs active at GABA type A receptors: the GABA-reuptake inhibitor tiagabine and a benzodiazepine, midazolam. The results demonstrate a synergistic protective effect of neurosteroid-tiagabine combinations, as well as neurosteroid-midazolam regimens in seizure models.

Thalamic GABA may modulate cognitive control in restless legs syndrome

The restless legs syndrome (RLS) has repeatedly, but not exclusively, been associated with functional thalamic changes as well as changes in GABAergic neurotransmission. This has been linked to the well-known sensory-motor symptoms, but it has never been investigated whether those factors also account for potential cognitive changes in RLS, even though they are known to play an important role for cognitive control. To investigate the potential relationship between thalamic GABA concentrations and cognitive control in n = 25 RLS patients; a neuropsychological experimental paradigm was used in combination with magnetic resonance spectroscopy (MRS). Compared to n = 31 healthy controls, RLS patients displayed reduced cognitive control capacities, which were most likely based on working memory deficits. On the neurobiochemical level, (relatively) elevated thalamic GABA levels attenuated control deficits only in the RLS group, even though there were no group differences with respect to overall GABA levels. Given that RLS patients are known to display thalamic hyperactivity and associated thalamic hypoconnectivity, (relatively) higher GABA levels may have helped RLS patients to “compensate” for this pathological factor. Our findings specify the functional relevance of thalamic GABAergic neurotransmission for cognition in RLS, even though changes in GABAergic neurotransmission might not be the ultimate cause of control deficits.

Activation of arcuate nucleus GABA neurons promotes luteinizing hormone secretion and reproductive dysfunction: Implications for polycystic ovary syndrome

BackgroundEnhanced GABA activity in the brain and a hyperactive hypothalamic-pituitary-gonadal axis are associated with polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Women with PCOS exhibit elevated cerebrospinal fluid GABA levels and preclinical models of PCOS exhibit increased GABAergic input to GnRH neurons, the central regulators of reproduction. The arcuate nucleus (ARN) is postulated as the anatomical origin of elevated GABAergic innervation; however, the functional role of this circuit is undefined. MethodsWe employed a combination of targeted optogenetic and chemogenetic approaches to assess the impact of acute and chronic ARN GABA neuron activation. Selective acute activation of ARN GABA neurons and their fiber projections was coupled with serial blood sampling for luteinizing hormone secretion in anesthetized male, female and prenatally androgenised (PNA) mice modelling PCOS. In addition, GnRH neuron responses to ARN GABA fiber stimulation were recorded in ex vivo brain slices. Chronic activation of ARN GABA neurons in healthy female mice was coupled with reproductive phenotyping for PCOS-like features. FindingsAcute stimulation of ARN GABA fibers adjacent to GnRH neurons resulted in a significant and long-lasting increase in LH secretion in male and female mice. The amplitude of this response was blunted in PNA mice, which also exhibited a blunted LH response to GnRH administration. Infrequent and variable GABAA-dependent changes in GnRH neuron firing were observed in brain slices. Chronic activation of ARN GABA neurons in healthy females impaired estrous cyclicity, decreased corpora lutea number and increased circulating testosterone levels. InterpretationARN GABA neurons can stimulate the hypothalamic-pituitary axis and chronic activation of ARN GABA neurons can mimic the reproductive deficits of PCOS in healthy females. Unexpectedly blunted HPG axis responses in PNA mice may reflect a history of high frequency GnRH/LH secretion and reduced LH stores, but also raise questions about impaired function within the ARN GABA population and the involvement of other circuits.

Evidence for the involvement of a GABAergic mechanism in the effectiveness of natural and synthetically modified incensole derivatives in neuropharmacological disorders: A computational and pharmacological approach

In the course of our continuing exploration for novel bioactive lead compounds (s) from the species Boswellia, we have recently reported incensole derivatives isolated from Boswellia papyrifera Hochst. Given the known antidepressant-like effects of incensole and incensole acetate, we herein present that the low dose intraperitoneal administration of incensole derivatives, namely, incensfuran and incensone, showed significant antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST). Furthermore, these compounds were evaluated for their anxiolytic potential in the elevated plus maze (EPM) and light dark box (LDB) tests and anticonvulsant effects in pentylenetetrazole (PTZ)-induced seizure tests. In the EPM test, administration of these compounds led to dose-dependent increases in open arm entries and in the time spent in EPM open arms. Similar results were obtained in the LDB test, wherein compounds these caused significant increases in the number of transitions between lit and dark compartments and the time spent in the lit compartment. The anxiolytic-like effects in the EPM were not reversed by pretreatment with flumazenil, whereas PTZ and bicuculline (BIC) completely abolished the anxiolytic effects, showing the involvement of the non-benzodiazepine binding sites of GABAA receptors. All four compounds induced significantly elevated brain GABA levels, indicating the involvement of a GABAergic mechanism. Additionally, molecular docking was conducted to elucidate the mode of action for the anxiolytic and anticonvulsant effects of these derivatives. Moreover, these compounds also possess drug-like properties and excellent ADMET profiles.

Abstract #149: Importance of Brain Volume on tDCS-induced Effects on GABA Levels

Introduction: Several aspects likely impact the effects of transcranial direct current stimulation (tDCS). One aspect that has not been explored very much is the impact of brain morphometry. The goal of this exploratory study was to test whether brain volume and thickness influence the effects of tDCS on neurotransmitter levels. We previously reported that real as compared to sham tDCS applied over bilateral dorsolateral prefrontal cortex (DLPFC) elevated GABA levels in the right DLPFC (under the anode electrode) in patients with gambling disorders (Dickler et al., 2018). Here, we further explored whether brain volume and thickness played a role on this tDCS effect.