Browsing by Subject "gamma-Aminobutyric Acid"

Now showing 1 - 9 of 9
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    Cancer-cell-derived GABA promotes β-catenin-mediated tumour growth and immunosuppression.
    (Nature cell biology, 2022-02) Huang, De; Wang, Yan; Thompson, J Will; Yin, Tao; Alexander, Peter B; Qin, Diyuan; Mudgal, Poorva; Wu, Haiyang; Liang, Yaosi; Tan, Lianmei; Pan, Christopher; Yuan, Lifeng; Wan, Ying; Li, Qi-Jing; Wang, Xiao-Fan
    Many cancers have an unusual dependence on glutamine. However, most previous studies have focused on the contribution of glutamine to metabolic building blocks and the energy supply. Here, we report that cancer cells with aberrant expression of glutamate decarboxylase 1 (GAD1) rewire glutamine metabolism for the synthesis of γ-aminobutyric acid (GABA)-a prominent neurotransmitter-in non-nervous tissues. An analysis of clinical samples reveals that increased GABA levels predict poor prognosis. Mechanistically, we identify a cancer-intrinsic pathway through which GABA activates the GABAB receptor to inhibit GSK-3β activity, leading to enhanced β-catenin signalling. This GABA-mediated β-catenin activation both stimulates tumour cell proliferation and suppresses CD8+ T cell intratumoural infiltration, such that targeting GAD1 or GABABR in mouse models overcomes resistance to anti-PD-1 immune checkpoint blockade therapy. Our findings uncover a signalling role for tumour-derived GABA beyond its classic function as a neurotransmitter that can be targeted pharmacologically to reverse immunosuppression.
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    Chronic Lyme disease: the controversies and the science.
    (Expert Rev Anti Infect Ther, 2011-07) Lantos, Paul M
    The diagnosis of chronic Lyme disease has been embroiled in controversy for many years. This is exacerbated by the lack of a clinical or microbiologic definition, and the commonality of chronic symptoms in the general population. An accumulating body of evidence suggests that Lyme disease is the appropriate diagnosis for only a minority of patients in whom it is suspected. In prospective studies of Lyme disease, very few patients go on to have a chronic syndrome dominated by subjective complaints. There is no systematic evidence that Borrelia burgdorferi, the etiology of Lyme disease, can be identified in patients with chronic symptoms following treated Lyme disease. Multiple prospective trials have revealed that prolonged courses of antibiotics neither prevent nor alleviate such post-Lyme syndromes. Extended courses of intravenous antibiotics have resulted in severe adverse events, which in light of their lack of efficacy, make them contraindicated.
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    Non-monotonic effects of GABAergic synaptic inputs on neuronal firing.
    (PLoS computational biology, 2022-06-06) Abed Zadeh, Aghil; Turner, Brandon D; Calakos, Nicole; Brunel, Nicolas
    GABA is generally known as the principal inhibitory neurotransmitter in the nervous system, usually acting by hyperpolarizing membrane potential. However, GABAergic currents sometimes exhibit non-inhibitory effects, depending on the brain region, developmental stage or pathological condition. Here, we investigate the diverse effects of GABA on the firing rate of several single neuron models, using both analytical calculations and numerical simulations. We find that GABAergic synaptic conductance and output firing rate exhibit three qualitatively different regimes as a function of GABA reversal potential, EGABA: monotonically decreasing for sufficiently low EGABA (inhibitory), monotonically increasing for EGABA above firing threshold (excitatory); and a non-monotonic region for intermediate values of EGABA. In the non-monotonic regime, small GABA conductances have an excitatory effect while large GABA conductances show an inhibitory effect. We provide a phase diagram of different GABAergic effects as a function of GABA reversal potential and glutamate conductance. We find that noisy inputs increase the range of EGABA for which the non-monotonic effect can be observed. We also construct a micro-circuit model of striatum to explain observed effects of GABAergic fast spiking interneurons on spiny projection neurons, including non-monotonicity, as well as the heterogeneity of the effects. Our work provides a mechanistic explanation of paradoxical effects of GABAergic synaptic inputs, with implications for understanding the effects of GABA in neural computation and development.
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    Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina.
    (PLoS biology, 2019-04) Grove, James CR; Hirano, Arlene A; de Los Santos, Janira; McHugh, Cyrus F; Purohit, Shashvat; Field, Greg D; Brecha, Nicholas C; Barnes, Steven
    The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.
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    Phenytoin, levetiracetam, and pregabalin in the acute management of refractory status epilepticus in patients with brain tumors.
    (Neurocrit Care, 2012-02) Swisher, Christa B; Doreswamy, Meghana; Gingrich, Krista J; Vredenburgh, James J; Kolls, Brad J
    BACKGROUND: There were nearly 700,000 patients in the United States in 2010 living with brain tumor diagnoses. The incidence of seizures in this population is as high as 70% and is historically difficult to control. Approximately 30-40% of brain tumors patients who present with status epilepticus (SE) will not respond to typical therapy consisting of benzodiazepines and phenytoin (PHT), resulting in patients with refractory status epilepticus (RSE). RSE is usually treated with anesthetic doses of propofol or midazolam infusions. This therapy can have significant risk, particularly in patients with cancer. METHODS: A retrospective chart review was performed on 23 patients with primary or metastatic brain tumors whose SE was treated with intravenous PHT, levetiracetam (LEV), and oral pregabalin (PGB). RESULTS: In all the patients under study, PHT or LEV was used as first-line therapy. PGB was typically used as third-line treatment. The median daily dose of PGB was 375 mg (usually divided BID or TID), and the median daily dose of LEV 3000 mg (usually divided BID). Cessation of SE was seen in 16/23 (70%) after administration of PHT, LEV, and PGB. SE was aborted, on average, 24 h after addition of the third antiepileptic drug. Only one patient in the responder group required intubation. Mortality rate was zero in the responder group. No adverse reactions to this medication regimen were observed. CONCLUSION: Our study suggests that the administration of PHT, LEV, and PGB in brain tumor patients with RSE is safe and highly effective.
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    Role of the midbrain dopaminergic system in modulation of vocal brain activation by social context.
    (Eur J Neurosci, 2007-06) Hara, Erina; Kubikova, Lubica; Hessler, Neal A; Jarvis, Erich D
    In a well-studied model of social behaviour, male zebra finches sing directed song to court females and undirected song, used possibly for practice or advertisement. Although the two song types are similar, the level of neural activity and expression of the immediate early gene egr-1 are higher during undirected than during directed singing in the lateral part of the basal ganglia song nucleus AreaX (LAreaX) and its efferent pallial song nuclei lateral magnocellular nucleus of the anterior nidopallium (LMAN) and the robust nucleus of the arcopallium (RA). As social interactions are dependent on brain motivation systems, here we test the hypothesis that the midbrain ventral tegmental area-substantia nigra pars compacta (VTA-SNc) complex, which provides a strong dopaminergic input to LAreaX, is a source of this modulation. Using egr-1 expression, we show that GABAergic interneurons in VTA-SNc are more active during directed courtship singing than during undirected singing. We also found that unilateral removal of VTA-SNc input reduced singing-dependent gene expression in ipsilateral LAreaX during both social contexts but it did not eliminate social context differences in LAreaX. In contrast, such lesions reduced and eliminated the social context differences in efferent nuclei LMAN and RA, respectively. These results suggest that VTA-SNc is not solely responsible for the social context gene regulation in LAreaX, but that VTA-SNc input to LAreaX enhances the singing-regulated gene expression in this nucleus and, either through LAreaX or through direct projections to LMAN and RA, VTA-SNc is necessary for context-dependent gene regulation in these efferent nuclei.
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    S-nitrosylation of GAD65 is implicated in decreased GAD activity and oxygen-induced seizures.
    (Neuroscience letters, 2017-07) Gasier, Heath G; Demchenko, Ivan T; Tatro, Lynn G; Piantadosi, Claude A
    Breathing oxygen at partial pressures ≥2.5 atmospheres absolute, which can occur in diving and hyperbaric oxygen (HBO2) therapy, can rapidly become toxic to the central nervous system (CNS). This neurotoxicity culminates in generalized EEG epileptiform discharges, tonic-clonic convulsions and ultimately death. Increased production of neuronal nitric oxide (NO) has been implicated in eliciting hyperoxic seizures by altering the equilibrium between glutamatergic and GABAergic synaptic transmission. Inhibition of glutamic acid decarboxylase (GAD) activity in HBO2 promotes this imbalance; however, the mechanisms by which this occurs is unknown. Therefore, we conducted a series of experiments using mice, a species that is highly susceptible to CNS oxygen toxicity, to explore the possibility that NO modulates GABA metabolism. Mice were exposed to 100% oxygen at 4 ATA for various durations, and brain GAD and GABA transaminase (GABA-T) activity, as well as S-nitrosylation of GAD65 and GAD67 were determined. HBO2 inhibited GAD activity by 50% and this was negatively correlated with S-nitrosylation of GAD65, whereas GABA-T activity and S-nitrosylation of GAD67 were unaltered. These results suggest a new mechanism by which NO alters GABA metabolism, leading to neuroexcitation and seizures in HBO2.
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    "Silent" NMDA Synapses Enhance Motion Sensitivity in a Mature Retinal Circuit.
    (Neuron, 2017-12) Sethuramanujam, Santhosh; Yao, Xiaoyang; deRosenroll, Geoff; Briggman, Kevin L; Field, Greg D; Awatramani, Gautam B
    Retinal direction-selective ganglion cells (DSGCs) have the remarkable ability to encode motion over a wide range of contrasts, relying on well-coordinated excitation and inhibition (E/I). E/I is orchestrated by a diverse set of glutamatergic bipolar cells that drive DSGCs directly, as well as indirectly through feedforward GABAergic/cholinergic signals mediated by starburst amacrine cells. Determining how direction-selective responses are generated across varied stimulus conditions requires understanding how glutamate, acetylcholine, and GABA signals are precisely coordinated. Here, we use a combination of paired patch-clamp recordings, serial EM, and large-scale multi-electrode array recordings to show that a single high-sensitivity source of glutamate is processed differentially by starbursts via AMPA receptors and DSGCs via NMDA receptors. We further demonstrate how this novel synaptic arrangement enables DSGCs to encode direction robustly near threshold contrasts. Together, these results reveal a space-efficient synaptic circuit model for direction computations, in which "silent" NMDA receptors play critical roles.
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    Use of pregabalin for nonconvulsive seizures and nonconvulsive status epilepticus.
    (Seizure, 2013-03) Swisher, Christa B; Doreswamy, Meghana; Husain, Aatif M
    PURPOSE: To determine the efficacy of pregabalin (PGB) in treatment of frequent nonconvulsive seizures (NCS) and nonconvulsive status epilepticus (NCSE) in critically ill patients. METHODS: In this retrospective study, 21 patients were identified as having received pregabalin for the treatment of NCS as determined by continuous electroencephalographic monitoring. The patients were considered to be responders if their seizures were terminated within 24h of initiation of PGB without the addition of another antiepileptic agent. RESULTS: Of the 21 patients who received PGB for treatment of NCS or NCSE, 11 (52%) were responders. PGB was administered via a nasogastric tube or orally and was the 2nd to 4th agent used. The average initial dose and total daily dose of PGB was similar in the responders and non-responders (342mg vs. 360mg, respectively). PGB was more effective in aborting NCS (9 patients, 82%) than NCSE (2 patients, 18%). Of the 9 brain tumor patients, PGB resulted in seizure cessation in 67% (6 patients). In contrast, all patients with hypoxic injury (4) did not respond to PGB. The responders were noted to have better clinical outcome (64% vs. 9% discharged home). Most of the patients tolerated the medication without any significant short term adverse effects, except two patients who were noted to have dizziness and sedation. CONCLUSIONS: Pregabalin may be safe option for add-on treatment for nonconvulsive seizures in critically ill patients when conventional therapy fails.