scholarly journals GABA receptors differentially regulate life span and health span in C. elegans through distinct downstream mechanisms

2019 ◽  
Vol 317 (5) ◽  
pp. C953-C963 ◽  
Author(s):  
Fengling Yuan ◽  
Jiejun Zhou ◽  
Lingxiu Xu ◽  
Wenxin Jia ◽  
Lei Chun ◽  
...  
Keyword(s):  
Life Span ◽  
Gaba Receptors ◽  
Health Span ◽  
Gaba A ◽  
Inhibitory Neurotransmitter ◽  
C Elegans ◽  
Physiological Processes ◽  
Gaba Signaling ◽  
Neuronal Functions

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors.

scholarly journals Temporal Transcriptomics of Gut Escherichia coli in Caenorhabditis elegans Models of Aging

2021 ◽  
Author(s):  
Joshua D. Brycki ◽  
Jeremy R. Chen See ◽  
Gillian R. Letson ◽  
Cade S. Emlet ◽  
Lavinia V. Unverdorben ◽  
...  
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Caenorhabditis Elegans ◽  
Life Span ◽  
Wild Type ◽  
Health Span ◽  
Content Type ◽  
C Elegans ◽  
Evolutionarily Conserved

Previous research has reported effects of the microbiome on health span and life span of Caenorhabditis elegans , including interactions with evolutionarily conserved pathways in humans. We build on this literature by reporting the gene expression of Escherichia coli OP50 in wild-type (N2) and three long-lived mutants of C. elegans .

scholarly journals Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 993
Author(s):  
Yuri Lee ◽  
Hyeseon Jeong ◽  
Kyung Hwan Park ◽  
Kyung Won Kim
Keyword(s):  
Caenorhabditis Elegans ◽  
Therapeutic Strategy ◽  
Axon Regeneration ◽  
Neuronal Damage ◽  
Biological Processes ◽  
Nematode Caenorhabditis Elegans ◽  
C Elegans ◽  
Neuronal Functions ◽  
Molecular Components

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

scholarly journals Is It Feasible of Prophylactic Alpha-5 GABA(A) Receptor Blockade for Preventing POCD?

2013 ◽  
Vol 3 (3) ◽  
pp. 61-62
Author(s):  
Fuzhou Wang
Keyword(s):  
Nervous System ◽  
General Anesthesia ◽  
Neuronal Excitability ◽  
Underlying Mechanism ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Inhibitory Neurotransmitter ◽  
Inhalational Anesthetics ◽  
Exploratory Data

GAMMA-AMINOBUTYRIC ACID (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system (CNS). It plays a role in regulating neuronal excitability throughout the nervous system. Also GABA activation is considered as the basis of general anesthesia including intravenous and inhalational anesthetics. Meanwhile, cumulating evidence indicated that GABA is the underlying mechanism of post-operative cognitive dysfunction (POCD). Based on these findings, researchers are beginning to focus on GABA as the target to treat POCD, but they ignored the role of GABA in the performance of general anesthesia, especially when the blockade of GABA was given prior to surgery. It is undoubtedly risking our patients in intra-operative awareness. Our exploratory data also verified our hypothesis in which the GABA inhibition would reduce the efficacy of inhalational anesthetics.

scholarly journals Oligodendroglial GABAergic Signaling: More Than Inhibition!

2021 ◽  
Author(s):  
Xianshu Bai ◽  
Frank Kirchhoff ◽  
Anja Scheller
Keyword(s):  
Gaba Receptors ◽  
Gaba Receptor ◽  
Signal Transmission ◽  
Physiological Role ◽  
Inhibitory Neurotransmitter ◽  
Short Summary ◽  
Central Synapses ◽  
G Protein Coupled ◽  
Shed Light

AbstractGABA is the main inhibitory neurotransmitter in the CNS acting at two distinct types of receptor: ligand-gated ionotropic GABAA receptors and G protein-coupled metabotropic GABAB receptors, thus mediating fast and slow inhibition of excitability at central synapses. GABAergic signal transmission has been intensively studied in neurons in contrast to oligodendrocytes and their precursors (OPCs), although the latter express both types of GABA receptor. Recent studies focusing on interneuron myelination and interneuron-OPC synapses have shed light on the importance of GABA signaling in the oligodendrocyte lineage. In this review, we start with a short summary on GABA itself and neuronal GABAergic signaling. Then, we elaborate on the physiological role of GABA receptors within the oligodendrocyte lineage and conclude with a description of these receptors as putative targets in treatments of CNS diseases.

scholarly journals Enhanced hippocampal type II theta activity AND altered theta architecture in mice lacking the Cav3.2 T-type voltage-gated calcium channel

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Muhammad Imran Arshaad ◽  
Magdalena Elisabeth Siwek ◽  
Christina Henseler ◽  
Johanna Daubner ◽  
Dan Ehninger ◽  
...  
Keyword(s):  
Gaba Receptors ◽  
Theta Activity ◽  
Type Ii ◽  
Dynein Light Chain ◽  
Gaba A ◽  
B1 Receptor ◽  
Transcriptional Changes ◽  
Hippocampal Theta

AbstractT-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2−/− mice revealed robust increase in relative power in the theta (4–8 Hz) and theta-alpha (4–12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2−/− mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2−/− mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.

scholarly journals The Role of Ca2+ Signaling in Aging and Neurodegeneration: Insights from Caenorhabditis elegans Models

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 204 ◽  
Author(s):  
Javier Alvarez ◽  
Pilar Alvarez-Illera ◽  
Paloma García-Casas ◽  
Rosalba I. Fonteriz ◽  
Mayte Montero
Keyword(s):  
Caenorhabditis Elegans ◽  
Model Organism ◽  
Ample Evidence ◽  
C Elegans ◽  
Physiological Processes ◽  
Human Proteins ◽  
Β Amyloid ◽  
Key Events

Ca2+ is a ubiquitous second messenger that plays an essential role in physiological processes such as muscle contraction, neuronal secretion, and cell proliferation or differentiation. There is ample evidence that the dysregulation of Ca2+ signaling is one of the key events in the development of neurodegenerative processes, an idea called the “calcium hypothesis” of neurodegeneration. Caenorhabditis elegans (C. elegans) is a very good model for the study of aging and neurodegeneration. In fact, many of the signaling pathways involved in longevity were first discovered in this nematode, and many models of neurodegenerative diseases have also been developed therein, either through mutations in the worm genome or by expressing human proteins involved in neurodegeneration (β-amyloid, α-synuclein, polyglutamine, or others) in defined worm tissues. The worm is completely transparent throughout its whole life, which makes it possible to carry out Ca2+ dynamics studies in vivo at any time, by expressing Ca2+ fluorescent probes in defined worm tissues, and even in specific organelles such as mitochondria. This review will summarize the evidence obtained using this model organism to understand the role of Ca2+ signaling in aging and neurodegeneration.

Abstract 224: Detoxification versus Healthy Aging: Aryl Hydrocarbon Receptor Deficiency Improves Vessel Functionality and Increases Healthy Lifespan

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Joachim Altschmied ◽  
Anna Eckers ◽  
Sascha Jakob ◽  
Christian Heiss ◽  
Christine Goy ◽  
...  
Keyword(s):  
Life Span ◽  
Aryl Hydrocarbon Receptor ◽  
Knockout Mice ◽  
Healthy Aging ◽  
Human Subjects ◽  
Surrogate Marker ◽  
Health Span ◽  
C Elegans ◽  
Aryl Hydrocarbon ◽  
Age Related

Development of age-associated vascular diseases like atherosclerosis depends not only on genetic predisposition but also on environmental influences. Ligands of the aryl hydrocarbon receptor (AhR), a ubiquitously expressed transcription factor upregulating detoxifying enzymes, like dioxin and benzo[a]pyrene (BaP) have been shown to promote atherosclerosis. Furthermore, recovery of the blood flow after hindlimb ischemia is significantly enhanced in AhR-deficient mice demonstrating increased angiogenesis in the absence of AhR. Thus, there seems to be a link between AhR, vessel functionality and age-related cardiovascular diseases. To investigate the role of the AhR in health span and vessel function, we analyzed AhR-deficient Caenorhabditis elegans, vessel stiffness in AhR-knockout mice and human subjects of different age and with varying levels of AhR expression as well as functional parameters in primary human endothelial cells (EC) after AhR activation. AhR-deficient C. elegans showed not only an extended life span, but also enhanced motility. In AhR-knockout mice, we observed a reduced PWV in both old and young animals, suggesting that AhR impairs vessel function already at young age. Concomitantly, eNOS phosphorylation at serine 1178, a surrogate marker for eNOS activation, was enhanced in aortas of knockout animals. In line with this, the AhR agonist BaP increased an inhibitory phosphorylation on eNOS in EC. Moreover, BaP reduced migration of EC without changes in proliferation or apoptosis, an effect that was reversed by addition of the AhR antagonist 3’methoxy-4’nitroflavone. In human subjects we demonstrated not only a positive correlation between age and pulse wave velocity (PWV), a readout for vessel stiffness, but also between AhR expression in blood cells and PWV, again suggesting a negative impact of AhR on vessel functionality. Our data demonstrate that loss of AhR extends life span as well as health span in C. elegans. Knockout of AhR in mice leads to improvement of vessel functionality by decreasing vessel stiffness. Finally, the PWV in humans positively correlates not only with age but also with the expression of AhR. Thus, AhR expression may be useful as a new predictor of healthy aging from nematodes to humans.

The role of GABA in modulating the Xenopus electroretinogram

1997 ◽  
Vol 14 (6) ◽  
pp. 1143-1152 ◽  
Author(s):  
Arsaell Arnarsson ◽  
Thor Eysteinsson
Keyword(s):  
Light Sensitivity ◽  
Gaba Uptake ◽  
Peak Time ◽  
Gamma Aminobutyric Acid ◽  
Nipecotic Acid ◽  
Gaba A ◽  
Inhibitory Neurotransmitter ◽  
Retinal Circuitry ◽  
Gaba Antagonist

AbstractWe have recorded the electroretinogram (ERG) from the superfused eyecup of the Xenopus retina in order to assess the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and its agonists and antagonists, on individual ERG components. We found that GABA (0.5–10 mM) reduced the amplitudes of both the b- and d-waves of the Xenopus ERG. The GABA uptake blocker nipecotic acid (1 mM) had similar effects on b- and d-waves. GABA at 5 mM and 10 mM also caused an increase in the a-wave. The GABA antagonist picrotoxin (0.1–2 mM) and the GABA/a antagonist bicuculline (0.2 mM) both increased the amplitude of the b- and d-waves of the ERG. The GABA/b agonist baclofen (0.3 mM) reduced the amplitude of the ERG b-wave, enhanced the amplitude of the a-wave, and slightly reduced the amplitude and increased the peak time of the d-wave. The GABA/b antagonists phaclofen and saclofen had no reliable effects on the Xenopus ERG. Glutamate analogs known to affect specific types of retinal neurons were applied to modify the retinal circuitry and then the effects of GABA and its antagonists were examined under these modified conditions. 2-amino-4-phosphonobutyric acid (APB) increased the d-wave, and blocked the b-wave and the effect of GABA on the ERG, but not the antagonist-induced increase in the d-wave. KYN blocked the antagonist-induced increase in the b-wave, while GABA increases the amplitude of the b-wave if the d-wave has been removed by prior superfusion with kynurenic acid (KYN). N-methyl-DL-aspartate (NMDLA), which acts only in the proximal retina, reduced the amplitude of the ERG and blocked the effect of GABA and the antagonist-induced increase in ERG b- and d-waves amplitude. These results suggest that GABAergic mechanisms related to both A and B receptor types can influence the amplitude and light sensitivity of all the components of the Xenopus ERG. Since GABA is found in greatest abundance in the proximal retina, and B type of receptors are present almost exclusively there, the data suggests that most of the effects of GABA agonists and antagonists observed are dependent on proximal retinal mechanisms, and that there are separate mechanisms in the proximal retina related to the b- and the d-waves.

scholarly journals Dietary unsaturated fatty acid metabolites modulate life span and health span of C. elegans

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Kin Sing Stephen Lee ◽  
Jamie Alan ◽  
Benjamin Kessler ◽  
Devon Dattmore ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Life Span ◽  
Unsaturated Fatty Acid ◽  
Health Span ◽  
C Elegans ◽  
Acid Metabolites ◽  
Fatty Acid Metabolites

scholarly journals Slc38a1 Conveys Astroglia-Derived Glutamine into GABAergic Interneurons for Neurotransmitter GABA Synthesis

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1686
Author(s):  
Tayyaba Qureshi ◽  
Mona Bjørkmo ◽  
Kaja Nordengen ◽  
Vidar Gundersen ◽  
Tor Paaske Utheim ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Brain Slices ◽  
Gabaergic Neurons ◽  
Action Potential Firing ◽  
Wide Range ◽  
Gaba Signaling ◽  
Potential Firing ◽  
Gaba Synthesis ◽  
Neuronal Functions

GABA signaling is involved in a wide range of neuronal functions, such as synchronization of action potential firing, synaptic plasticity and neuronal development. Sustained GABA signaling requires efficient mechanisms for the replenishment of the neurotransmitter pool of GABA. The prevailing theory is that exocytotically released GABA may be transported into perisynaptic astroglia and converted to glutamine, which is then shuttled back to the neurons for resynthesis of GABA—i.e., the glutamate/GABA-glutamine (GGG) cycle. However, an unequivocal demonstration of astroglia-to-nerve terminal transport of glutamine and the contribution of astroglia-derived glutamine to neurotransmitter GABA synthesis is lacking. By genetic inactivation of the amino acid transporter Solute carrier 38 member a1 (Slc38a1)—which is enriched on parvalbumin+ GABAergic neurons—and by intraperitoneal injection of radiolabeled acetate (which is metabolized to glutamine in astroglial cells), we show that Slc38a1 mediates import of astroglia-derived glutamine into GABAergic neurons for synthesis of GABA. In brain slices, we demonstrate the role of Slc38a1 for the uptake of glutamine specifically into GABAergic nerve terminals for the synthesis of GABA depending on demand and glutamine supply. Thus, while leaving room for other pathways, our study demonstrates a key role of Slc38a1 for newly formed GABA, in harmony with the existence of a GGG cycle.

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