Glutamatergic receptors at developing synapses: The role of GluN3A-containing NMDA receptors and GluA2-lacking AMPA receptors

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.

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

Journal of Neurophysiology ◽

10.1152/jn.00725.2010 ◽

2011 ◽

Vol 105 (2) ◽

pp. 923-928 ◽

Cited By ~ 14

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.

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

Journal of Neurophysiology ◽

10.1152/jn.00201.2005 ◽

2005 ◽

Vol 94 (6) ◽

pp. 3951-3960 ◽

Cited By ~ 27

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.

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

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2017-0010 ◽

2019 ◽

Vol 20 (1) ◽

pp. 3-13 ◽

Cited By ~ 1

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.

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