scholarly journals When Are Depolarizing GABAergic Responses Excitatory?

2021 ◽  
Vol 14 ◽  
Author(s):  
Werner Kilb
Keyword(s):  
Neuronal Excitability ◽  
Neuronal Development ◽  
Developmental Stages ◽  
Experimental Studies ◽  
Reversal Potential ◽  
Input Resistance ◽  
Gaba A ◽  
Theoretical Considerations

The membrane responses upon activation of GABA(A) receptors critically depend on the intracellular Cl− concentration ([Cl−]i), which is maintained by a set of transmembrane transporters for Cl−. During neuronal development, but also under several pathophysiological conditions, the prevailing expression of the Cl− loader NKCC1 and the low expression of the Cl− extruder KCC2 causes elevated [Cl−]i, which result in depolarizing GABAergic membrane responses. However, depolarizing GABAergic responses are not necessarily excitatory, as GABA(A) receptors also reduces the input resistance of neurons and thereby shunt excitatory inputs. To summarize our knowledge on the effect of depolarizing GABA responses on neuronal excitability, this review discusses theoretical considerations and experimental studies illustrating the relation between GABA conductances, GABA reversal potential and neuronal excitability. In addition, evidences for the complex spatiotemporal interaction between depolarizing GABAergic and glutamatergic inputs are described. Moreover, mechanisms that influence [Cl−]i beyond the expression of Cl− transporters are presented. And finally, several in vitro and in vivo studies that directly investigated whether GABA mediates excitation or inhibition during early developmental stages are summarized. In summary, these theoretical considerations and experimental evidences suggest that GABA can act as inhibitory neurotransmitter even under conditions that maintain substantial depolarizing membrane responses.

Effects of norepinephrine upon superficial layer neurons in the superior colliculus of the hamster: In vitro studies

1999 ◽  
Vol 16 (3) ◽  
pp. 557-570 ◽  
Author(s):  
HONGJING TAN ◽  
RICHARD D. MOONEY ◽  
ROBERT W. RHOADES
Keyword(s):  
Superior Colliculus ◽  
Optic Tract ◽  
Reversal Potential ◽  
Outward Current ◽  
Input Resistance ◽  
Superficial Layer ◽  
Membrane Properties ◽  
Induced Response

Intracellular recording techniques were used to evaluate the effects of norepinephrine (NE) on the membrane properties of superficial layer (stratum griseum superficiale and stratum opticum) superior colliculus (SC) cells. Of the 207 cells tested, 44.4% (N = 92) were hyperpolarized by ≥3 mV and 8.7% (N = 18) were depolarized by ≥3 mV by application of NE. Hyperpolarization induced by NE was dose dependent (EC50 = 8.1 μM) and was associated with decreased input resistance and outward current which had a reversal potential of −94.0 mV. Depolarization was associated with a very slight rise in input resistance and had a reversal potential of −93.1 mV for the single cell tested. Pharmacologic experiments demonstrated that isoproterenol, dobutamine, and p-aminoclonidine all hyperpolarized SC cells. These results are consistent with the conclusion that NE-induced hyperpolarization of SC cells is mediated by both α2 and β1 adrenoceptors. The α1 adrenoceptor agonists, methoxamine and phenylephrine, depolarized 35% (6 of 17) of the SC cells tested by ≥3 mV. Most of the SC cells tested exhibited responses indicative of expression of more than one adrenoceptor. Application of p-aminoclonidine or dobutamine inhibited transsynaptic responses in SC cells evoked by electrical stimulation of optic tract axons. Inhibition of evoked responses by these agents was usually, but not invariably, associated with a hyperpolarization of the cell membrane and a reduction in depolarizing potentials evoked by application of glutamate. The present in vitro results are consistent with those of the companion in vivo study which suggested that NE-induced response suppression in superficial layer SC neurons was primarily postsynaptic and chiefly mediated by both α2 and β1 adrenoceptors.

scholarly journals The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.

2018 ◽  
Author(s):  
Petra Spirhanzlova ◽  
Sebastien Le Mevel ◽  
Karn Wejaphikul ◽  
Bilal Mughal ◽  
Jean-David Gothie ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Neuronal Development ◽  
Daily Intake ◽  
Experimental Studies ◽  
Binding Pocket ◽  
In Vitro Assays ◽  
Reporter System ◽  
Induced Changes

Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-PPF (> 3 mg/L ) to act as a TRα antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4'OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse neurosphere cultures, environmentally relevant concentrations of 4'OH-PPF increased expression of the gene that enables ZIKA replication: Musashi-1 (msi1) in neurogenic brain areas. We conclude that first, the PPF metabolite, 4'OH-PPF, disrupts thyroid signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to enhance viral replication. As PPF is used in areas with high microcephaly incidence and is readily broken down to 4'OH-PPF, these findings provide a plausible mechanism whereby PPF could, through induced changes in expression of Musashi-1, exacerbate the effects of ZIKA virus infection.

Effect of cholinergic agonists on bulbospinal C1 neurons in rats

1997 ◽  
Vol 272 (1) ◽  
pp. R249-R258 ◽  
Author(s):  
D. Huangfu ◽  
M. Schreihofer ◽  
P. G. Guyenet
Keyword(s):  
Brain Slices ◽  
Reversal Potential ◽  
Input Resistance ◽  
Neonatal Rat ◽  
Ventrolateral Medulla ◽  
Cholinergic Agonists ◽  
Inward Currents ◽  
Tone Generation

Cholinergic inputs to the rostral ventrolateral medulla (RVLM) may contribute to sympathetic tone generation. The present study analyzes the response of RVLM neurons to cholinergic agonists. In chloralose-anesthetized rats iontophoresis of carbachol excited RVLM sympathoexcitatory neurons (+69% from resting level of 11.9 +/- 2 spikes/s; n = 28). This effect was reduced 85% by iontophoresis of methylatropine and abolished by intravenous scopolamine. Iontophoresis of nicotine or hexamethonium was ineffective. In contrast, most RVLM respiratory units were inhibited by carbachol. Whole cell recordings of bulbospinal RVLM neurons were made in neonatal rat brain slices (54 cells, 24 C1 adrenergic neurons). In current-clamp recordings (without tetrodotoxin) carbachol produced depolarization, increased postsynaptic potential frequency, and decreased input resistance. In voltage-clamp recording (-50 to -60 mV; 1 microM tetrodotoxin) carbachol produced inward current [50% effective concentration (EC50): 10 +/- 1 microM; 12.6 +/- 2 pA at 30 microM; n = 16] that persisted in low Ca2+/high Mg2+ (n = 6). Muscarine (30 microM) caused smaller inward currents (2.6 +/- 0.6 pA; n = 16). The carbachol-induced current was reduced 46% by 5 microM methylatropine (n = 15) and 84% by 200 microM hexamethonium (n = 9). The current was linear as a function of the holding potential (extrapolated reversal potential: -22 +/- 2 mV). In conclusion, carbachol exerts both pre- and postsynaptic effects on C1 and other putative sympathoexcitatory RVLM neurons. In vitro the postsynaptic effect of carbachol has a mixed nicotinic and muscarinic pharmacology. In vivo, iontophoretically applied carbachol produces muscarinic excitation of barosensitive RVLM neurons.

scholarly journals Genome-Wide Transcriptomic Identification and Functional Insight of Lily WRKY Genes Responding to Botrytis Fungal Disease

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 776
Author(s):  
Shipra Kumari ◽  
Bashistha Kumar Kanth ◽  
Ju young Ahn ◽  
Jong Hwa Kim ◽  
Geung-Joo Lee
Keyword(s):  
Abiotic Stress ◽  
Biotic Stress ◽  
Developmental Stages ◽  
Expression Patterns ◽  
Lilium Longiflorum ◽  
Biotic And Abiotic Stress ◽  
Biotic Stresses ◽  
Genome Wide

Genome-wide transcriptome analysis using RNA-Seq of Lilium longiflorum revealed valuable genes responding to biotic stresses. WRKY transcription factors are regulatory proteins playing essential roles in defense processes under environmental stresses, causing considerable losses in flower quality and production. Thirty-eight WRKY genes were identified from the transcriptomic profile from lily genotypes, exhibiting leaf blight caused by Botrytis elliptica. Lily WRKYs have a highly conserved motif, WRKYGQK, with a common variant, WRKYGKK. Phylogeny of LlWRKYs with homologous genes from other representative plant species classified them into three groups- I, II, and III consisting of seven, 22, and nine genes, respectively. Base on functional annotation, 22 LlWRKY genes were associated with biotic stress, nine with abiotic stress, and seven with others. Sixteen unique LlWRKY were studied to investigate responses to stress conditions using gene expression under biotic and abiotic stress treatments. Five genes—LlWRKY3, LlWRKY4, LlWRKY5, LlWRKY10, and LlWRKY12—were substantially upregulated, proving to be biotic stress-responsive genes in vivo and in vitro conditions. Moreover, the expression patterns of LlWRKY genes varied in response to drought, heat, cold, and different developmental stages or tissues. Overall, our study provides structural and molecular insights into LlWRKY genes for use in the genetic engineering in Lilium against Botrytis disease.

scholarly journals A Review on the Medicinal and Pharmacological Properties of Traditional Ethnomedicinal Plant Sonapatha, Oroxylum indicum

Sinusitis ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 71-89
Author(s):  
Ganesh Chandra Jagetia
Keyword(s):  
Glucose Transporter ◽  
Skin Diseases ◽  
Regulatory Element ◽  
Experimental Studies ◽  
Fatty Acid Synthetase ◽  
Preclinical Models ◽  
Oroxylin A ◽  
Oroxylum Indicum

Oroxylum indicum, Sonapatha is traditionally used to treat asthma, biliousness, bronchitis, diarrhea, dysentery, fevers, vomiting, inflammation, leukoderma, skin diseases, rheumatoid arthritis, wound injury, and deworm intestine. This review has been written by collecting the relevant information from published material on various ethnomedicinal and pharmacological aspects of Sonapatha by making an internet, PubMed, SciFinder, Science direct, and Google Scholar search. Various experimental studies have shown that Sonapatha scavenges different free radicals and possesses alkaloids, flavonoids, cardio glycosides, tannins, sterols, phenols, saponins, and other phytochemicals. Numerous active principles including oroxylin A, chrysin, scutellarin, baicalein, and many more have been isolated from the different parts of Sonapatha. Sonapatha acts against microbial infection, cancer, hepatic, gastrointestinal, cardiac, and diabetic disorders. It is useful in the treatment of obesity and wound healing in in vitro and in vivo preclinical models. Sonapatha elevates glutathione, glutathione-s-transferase, glutathione peroxidase, catalase, and superoxide dismutase levels and reduces aspartate transaminase alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and lipid peroxidation levels in various tissues. Sonapatha activates the expression of p53, pRb, Fas, FasL, IL-12, and caspases and inhibited nuclear factor kappa (NF-κB), cyclooxygenase (COX-2), tumor necrosis factor (TNFα), interleukin (IL6), P38 activated mitogen-activated protein kinases (MAPK), fatty acid synthetase (FAS), sterol regulatory element-binding proteins 1c (SREBP-1c), proliferator-activated receptor γ2 (PPARγ2), glucose transporter (GLUT4), leptin, and HPV18 oncoproteins E6 and E7 at the molecular level, which may be responsible for its medicinal properties. The phytoconstituents of Sonapatha including oroxylin A, chrysin, and baicalein inhibit the replication of SARS-CoV-2 (COVID-19) in in vitro and in vivo experimental models, indicating its potential to contain COVID-19 infection in humans. The experimental studies in various preclinical models validate the use of Sonapatha in ethnomedicine and Ayurveda.

scholarly journals Melatonin in Cancer Treatment: Current Knowledge and Future Opportunities

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2506
Author(s):  
Wamidh H. Talib ◽  
Ahmad Riyad Alsayed ◽  
Alaa Abuawad ◽  
Safa Daoud ◽  
Asma Ismail Mahmod
Keyword(s):  
Clinical Trials ◽  
Current Knowledge ◽  
Biological Activities ◽  
Experimental Studies ◽  
Therapeutic Effects ◽  
Cell Proliferation Inhibition ◽  
Different Types ◽  
Solid Foundation

Melatonin is a pleotropic molecule with numerous biological activities. Epidemiological and experimental studies have documented that melatonin could inhibit different types of cancer in vitro and in vivo. Results showed the involvement of melatonin in different anticancer mechanisms including apoptosis induction, cell proliferation inhibition, reduction in tumor growth and metastases, reduction in the side effects associated with chemotherapy and radiotherapy, decreasing drug resistance in cancer therapy, and augmentation of the therapeutic effects of conventional anticancer therapies. Clinical trials revealed that melatonin is an effective adjuvant drug to all conventional therapies. This review summarized melatonin biosynthesis, availability from natural sources, metabolism, bioavailability, anticancer mechanisms of melatonin, its use in clinical trials, and pharmaceutical formulation. Studies discussed in this review will provide a solid foundation for researchers and physicians to design and develop new therapies to treat and prevent cancer using melatonin.

scholarly journals Histone/protein deacetylases and T-cell immune responses

Blood ◽  
2012 ◽  
Vol 119 (11) ◽  
pp. 2443-2451 ◽  
Author(s):  
Tatiana Akimova ◽  
Ulf H. Beier ◽  
Yujie Liu ◽  
Liqing Wang ◽  
Wayne W. Hancock
Keyword(s):  
T Cell ◽  
Cell Biology ◽  
T Regulatory Cells ◽  
Hdac Inhibitors ◽  
Experimental Studies ◽  
Cell Subset ◽  
Histone Protein ◽  
Anti Inflammatory

Abstract Clinical and experimental studies show that inhibition of histone/protein deacetylases (HDAC) can have important anti-neoplastic effects through cytotoxic and proapoptotic mechanisms. There are also increasing data from nononcologic settings that HDAC inhibitors (HDACi) can exhibit useful anti-inflammatory effects in vitro and in vivo, unrelated to cytotoxicity or apoptosis. These effects can be cell-, tissue-, or context-dependent and can involve modulation of specific inflammatory signaling pathways as well as epigenetic mechanisms. We review recent advances in the understanding of how HDACi alter immune and inflammatory processes, with a particular focus on the effects of HDACi on T-cell biology, including the activation and functions of conventional T cells and the unique T-cell subset, composed of Foxp3+ T-regulatory cells. Although studies are still needed to tease out details of the various biologic roles of individual HDAC isoforms and their corresponding selective inhibitors, the anti-inflammatory effects of HDACi are already promising and may lead to new therapeutic avenues in transplantation and autoimmune diseases.

scholarly journals Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Andreas Pollreisz ◽  
Ursula Schmidt-Erfurth
Keyword(s):  
Experimental Studies ◽  
Disease Process ◽  
Basic Research ◽  
Polyol Pathway ◽  
Population Based ◽  
Diabetic Patients ◽  
Diabetic Cataract ◽  
Cataract Development

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.

scholarly journals Experimental studies on the differentiation of embryonic tissues growing in vivo and in vitro .—II. The development of the isolated early embryonic eye of the fowl when cultivated in vitro

1926 ◽  
Vol 100 (703) ◽  
pp. 273-283 ◽  
Keyword(s):  
Medical Research ◽  
Research Council ◽  
Medical Research Council ◽  
Experimental Studies ◽  
Limb Bud ◽  
Progressive Development ◽  
Embryonic Tissues ◽  
Self Differentiation

In a previous communication (Strangeways and Fell, 1926) it was shown that if the undifferentiated limb-bud of the embryonic Fowl was cultivated in vitro , it underwent a considerable amount of progressive development. This capacity for independent development in vitro possessed by an isolated organ has been further investigated, and for these later experiments the writers have employed the early embryonic eye, a structure endowed with more complex potentialities than the limb-bud. As a result of these experiments it was found that the eyes of young Fowl embryos possess, in a remarkable degree, the faculty for self-differentiation in vitro and for “organotypic” growth as defined by Maximow (1925). The previous work on organotypic growth in vitro has already been briefly outlined in the writers’ earlier paper and need not be discussed here. The expenses connected with the experiments described in this communication were met by the Medical Research Council, to whom the writers desire to express their thanks.

Regulation of expression of mRNAs encoding the nerve growth factor receptors p75 and trkA in developing sensory neurons

Development ◽  
1993 ◽  
Vol 119 (3) ◽  
pp. 635-648 ◽  
Author(s):  
S. Wyatt ◽  
A.M. Davies
Keyword(s):  
Neuronal Development ◽  
Polymerase Chain Reaction Amplification ◽  
Mrna Levels ◽  
Regulation Of Expression ◽  
Trigeminal Neurons ◽  
Nerve Growth Factor Receptors ◽  
Reaction Amplification ◽  
Amplification Technique

We have used a quantitative reverse transcription/polymerase chain reaction amplification technique to study the regulation of p75 mRNA and trkA mRNA expression in developing NGF-dependent trigeminal neurons. Before becoming NGF dependent, these neurons express low levels of p75 and trkA mRNAs in vivo. At this stage in vitro, the level of p75 mRNA is maintained and up-regulated by BDNF, whereas the level of trkA mRNA is sustained independently of neurotrophins and is down-regulated by BDNF. With the acquisition of NGF dependence, p75 and trkA mRNA levels increase markedly in vivo. At this stage in vitro, the level of p75 mRNA is up-regulated by NGF, but this response is lost at later stages. The level of trkA mRNA is sustained in neurons grown with NGF but is not up-regulated by concentrations of NGF above those required to support survival. At no stage during the early development of trigeminal neurons do depolarising levels of potassium ions affect the expression of either p75 mRNA or trkA mRNA. These findings suggest that the expression of p75 and trkA mRNAs are differentially regulated by BDNF and NGF at successive early stages of neuronal development.

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