scholarly journals Potentiation of Synaptic AMPA Receptors Induced by the Deletion of NMDA Receptors Requires the GluA2 Subunit

2011 ◽  
Vol 105 (2) ◽  
pp. 923-928 ◽  
Author(s):  
Wei Lu ◽  
John A. Gray ◽  
Adam J. Granger ◽  
Matthew J. During ◽  
Roger A. Nicoll
Keyword(s):  
Nmda Receptors ◽  
Single Cell ◽  
Ampa Receptors ◽  
Substantial Evidence ◽  
Ampar Trafficking

Deletion of N-methyl-d-aspartate receptors (NMDARs) early in development results in an increase in the number of synaptic AMPA receptors (AMPARs), suggesting a role for NMDARs in negatively regulating AMPAR trafficking at developing synapses. Substantial evidence has shown that AMPAR subunits function differentially in AMPAR trafficking. However, the role of AMPAR subunits in the enhancement of AMPARs following NMDAR ablation remains unknown. We have now performed single-cell genetic deletions in double-floxed mice in which the deletion of GluN1 is combined with the deletion of GluA1 or GluA2. We find that the AMPAR enhancement following NMDAR deletion requires the GluA2 subunit, but not the GluA1 subunit, indicating a key role for GluA2 in the regulation of AMPAR trafficking in developing synapses.

Analysis of the Role of Inhibition in Shaping Responses to Sinusoidally Amplitude-Modulated Signals in the Inferior Colliculus

1998 ◽  
Vol 80 (4) ◽  
pp. 1686-1701 ◽  
Author(s):  
R. Michael Burger ◽  
George D. Pollak
Keyword(s):  
Nmda Receptors ◽  
Inferior Colliculus ◽  
Ampa Receptors ◽  
Phase Locking ◽  
Receptor Blocker ◽  
Response Property ◽  
Medial Superior Olive ◽  
Competitive Antagonist ◽  
Modulated Signals

Burger, R. Michael and George D. Pollak. Analysis of the role of inhibition in shaping responses to sinusoidally amplitude-modulated signals in the inferior colliculus. J. Neurophysiol. 80: 1686–1701, 1998. Neurons in the central nucleus of the inferior colliculus (ICc) typically respond with phase-locked discharges to low rates of sinusoidal amplitude-modulated (SAM) signals and fail to phase-lock to higher SAM rates. Previous studies have shown that comparable phase-locking to SAM occurs in the dorsal nucleus of the lateral lemniscus (DNLL) and medial superior olive (MSO) of the mustache bat. The studies of MSO and DNLL also showed that the restricted phase-locking to low SAM rates is created by the coincidence of phase-locked excitatory and inhibitory inputs that have slightly different latencies. Here we tested the hypothesis that responses to SAM in the mustache bat IC are shaped by the same mechanism that shapes responses to SAM in the two lower nuclei. We recorded responses from ICc neurons evoked by SAM signals before and during the iontophoretic application of several pharmacological agents: bicuculline, a competitive antagonist for γ-aminobutyric acid-A (GABAA) receptors; strychnine, a competitive antagonist for glycine receptors; the GABAB receptor blocker, phaclofen, and the N-methyl-d-aspartate (NMDA) receptor blocker, (−)-2-amino-5-phosphonopentanoic acid (AP5). The hypothesis that inhibition shapes responses to SAM signals in the ICc was not confirmed. In >90% of the ICc neurons tested, the range of SAM rates to which they phase-locked was unchanged after blocking inhibition with bicuculline, strychnine or phaclofen, applied either individually or in combination. We also considered the possibility that faster α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors follow high temporal rates of incoming excitation but that the slower NMDA receptors could follow only lower rates. Thus at higher SAM rates, NMDA receptors might generate a sustained excitation that “smears” the phase-locked excitation generated by the AMPA receptors. The NMDA hypothesis, like the inhibition hypothesis, was also not confirmed. In none of the cells that we tested did the application of AP5 by itself, or in combination with bicuculline, cause an increase in the range of SAM rates that evoked phase-locking. These results illustrate that the same response property, phase-locking restricted to low SAM rates, is formed in more than one way in the auditory brain stem. In the MSO and DNLL, the mechanism is coincidence of phase-locked excitation and inhibition, whereas in ICc the same response feature is formed by a different but unknown mechanism.

Role of AMPA Receptor Desensitization and the Side Effects of a DMSO Vehicle on Reticulospinal EPSPs and Locomotor Activity

2005 ◽  
Vol 94 (6) ◽  
pp. 3951-3960 ◽  
Author(s):  
Nataliya A. Tsvyetlynska ◽  
Russell H. Hill ◽  
Sten Grillner
Keyword(s):  
Nmda Receptors ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Pattern Generation ◽  
Network Activity ◽  
Excitatory Postsynaptic Potential ◽  
Receptor Desensitization ◽  
Neuronal Network Activity ◽  
The Brain

Activation of the vertebrate locomotor network is mediated by glutamatergic synaptic drive, normally initiated by the brain stem. Previous investigations have studied the role of glutamate receptors, especially NMDA receptors, in generating and regulating locomotor pattern generation. Few studies, however, have focused on the role of AMPA receptors in shaping network activity, especially with regard to their rapid desensitization. It is important to determine whether AMPA receptor desensitization plays a role in regulating neuronal network activity. We examined this question on both the network and synaptic levels in the lamprey ( Lampetra fluviatilis) spinal cord using a selective and potent inhibitor of AMPA receptor desensitization, cyclothiazide (CTZ). The solvent dimethyl sulfoxide (DMSO) is commonly used to dissolve this drug, as well as many others. Unexpectedly, the vehicle alone already at 0.02%, but not at 0.01%, caused significant increases in excitatory postsynaptic potential (EPSP) amplitudes and NMDA-induced locomotor frequency. The results indicate that DMSO may have a profound influence when used ≥0.02%, a concentration 10–50 times less than that most commonly used. Subsequently we applied CTZ concentrations ≤10 μM (DMSO ≤0.01%). CTZ (1.25–5 μM) caused an appreciable and significant increase in EPSPs mediated by non-NMDA receptors and in both AMPA- and NMDA-induced locomotor frequency, but no effects on EPSPs mediated by NMDA receptors. From the effects of CTZ it is apparent that AMPA receptor desensitization plays an important role in determining locomotor frequency and that this is likely a result of its limiting function on AMPA receptor–mediated EPSPs.

scholarly journals Possible Role of N-Methyl-D-Aspartate Receptors in Physiology and Pathophysiology of Cardiovascular System

2019 ◽  
Vol 20 (1) ◽  
pp. 3-13 ◽  
Author(s):  
Ivan Srejovic ◽  
Vladimir Jakovljevic ◽  
Vladimir Zivkovic ◽  
Dragan Djuric
Keyword(s):  
Nmda Receptors ◽  
Cardiovascular System ◽  
Ampa Receptors ◽  
Heart Function ◽  
Cell Types ◽  
Receptor Activation ◽  
Simultaneous Action ◽  
Cardiovascular Disorders ◽  
Voltage Dependent

Abstract N-methyl-D-aspartate (NMDA) receptors belong to ionotropic glutamate receptor family, together with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, kainite receptors and δ-receptors. All of these receptors are tetramers composed of four subunits. NMDA receptors have several unique features in relation to other ionotropic glutamate receptors: requirement for simultaneous action of two coagonists, glutamate and glycine; dual control of receptor activation, ligand-dependent (by glutamate and glycine) and voltage-dependent (Mg2+ block) control; and influx of considerable amounts of Ca2+ following receptor activation. Increasing number of researches deals with physiological and pathophysiological roles of NMDA receptors outside of nerve tissues, especially in the cardiovascular system. NMDA receptors are found in all cell types represented in cardiovascular system, and their overstimulation in pathological conditions, such as hyperhomocysteinemia, is related to a range of cardiovascular disorders. On the other hand we demonstrated that blockade of NMDA receptors depresses heart function. There is a need for the intensive study of NMDA receptor in cardiovascular system as potential theraputical target both in prevention and treatment of cardiovascular disorders.

The Role of Quercetin in Gene Expression of GluR1 Subunit of AMPA Receptors, and NR2A and NR2B Subunits of NMDA Receptors in Kainic Acid Model of Seizure in Mice

2016 ◽  
Vol 19 (5) ◽  
Author(s):  
Sahar Moghbelinejad ◽  
Ghazaleh Mohammadi ◽  
Fatemeh Khodabandehloo ◽  
Reza Najafipour ◽  
Taghi Naserpour ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nmda Receptors ◽  
Kainic Acid ◽  
Ampa Receptors ◽  
Glur1 Subunit

scholarly journals Histomorphological Assessment of Formalin versus Nonformalin Fixatives in Diagnostic Surgical Pathology

2020 ◽  
Vol 12 (04) ◽  
pp. 271-275
Author(s):  
Jayaprakash Kubalady Shetty ◽  
Hannah Fathima Babu ◽  
Kishan Prasad Hosapatna Laxminarayana
Keyword(s):  
Methyl Alcohol ◽  
Potential Role ◽  
Tissue Architecture ◽  
Substantial Evidence ◽  
Diagnostic Pathology ◽  
Rapid Fixation ◽  
Chromatin Texture ◽  
Upper Respiratory ◽  
Potential Human Health

Abstract Introduction Fixation is the critical step in the preservation of tissues in diagnostic pathology. The formalin is an economical and excellent fixative with the inherent property of adequate fixation. The well-established side effects of formalin include mucosal irritation, upper respiratory diseases, and corrosive injury to the gastrointestinal tract. In addition, substantial evidence exists regarding the potential role of formaldehyde as a human carcinogen. The carcinogenic and toxic effects of formalin encourage searching for alternative fixatives for tissue fixation. However, “the formalin dogma” has severely hampered the search for alternative fixatives for many years. Material and Methods Ninety tissues of liver and skeletal muscle obtained during autopsies were immersed in adequate amounts of the following fixatives: formalin (10%), methyl alcohol (70%), and acetone (100%). The comparison among the three was made based on time for fixation, preservation of tissue architecture, cell borders, cytoplasm, nuclear contours, chromatin texture, and uniformity of staining. Results The tissue preserved in formalin undergoes rapid fixation compared with alcohol and acetone. The tissue architecture, cell border characteristics of alcohol and acetone was found satisfactory compared with formalin. The cytoplasm and nuclear contour were superior with the formalin. The chromatin texture and uniformity of staining were similar with all the three fixatives. Conclusion The formalin is considered superior to most of the parameters, whereas both methyl alcohol and acetone showed nearly equivalent scores. Hence, owing to the potential human health hazards and carcinogenicity of formalin, no rational reasons hamper the complete substitution of formalin with alternative fixatives such as alcohol and acetone in diagnostic pathology and medical research.

scholarly journals Optimizing expression quantitative trait locus mapping workflows for single-cell studies

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Anna S. E. Cuomo ◽  
Giordano Alvari ◽  
Christina B. Azodi ◽  
Davis J. McCarthy ◽  
Marc Jan Bonder ◽  
...  
Keyword(s):  
Gene Expression ◽  
Quantitative Trait Locus ◽  
Single Cell ◽  
Quantitative Trait ◽  
Cell Types ◽  
Expression Quantitative Trait Locus ◽  
Eqtl Mapping ◽  
Trait Locus ◽  
The Impact

Abstract Background Single-cell RNA sequencing (scRNA-seq) has enabled the unbiased, high-throughput quantification of gene expression specific to cell types and states. With the cost of scRNA-seq decreasing and techniques for sample multiplexing improving, population-scale scRNA-seq, and thus single-cell expression quantitative trait locus (sc-eQTL) mapping, is increasingly feasible. Mapping of sc-eQTL provides additional resolution to study the regulatory role of common genetic variants on gene expression across a plethora of cell types and states and promises to improve our understanding of genetic regulation across tissues in both health and disease. Results While previously established methods for bulk eQTL mapping can, in principle, be applied to sc-eQTL mapping, there are a number of open questions about how best to process scRNA-seq data and adapt bulk methods to optimize sc-eQTL mapping. Here, we evaluate the role of different normalization and aggregation strategies, covariate adjustment techniques, and multiple testing correction methods to establish best practice guidelines. We use both real and simulated datasets across single-cell technologies to systematically assess the impact of these different statistical approaches. Conclusion We provide recommendations for future single-cell eQTL studies that can yield up to twice as many eQTL discoveries as default approaches ported from bulk studies.

scholarly journals Astrocytes and neuroinflammation in Alzheimer's disease

2014 ◽  
Vol 42 (5) ◽  
pp. 1321-1325 ◽  
Author(s):  
Emma C. Phillips ◽  
Cara L. Croft ◽  
Ksenia Kurbatskaya ◽  
Michael J. O’Neill ◽  
Michael L. Hutton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Responses ◽  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Substantial Evidence ◽  
Models Of Disease ◽  
Opposing Effects

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.

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