Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

A synaptic model of memory: long-term potentiation in the hippocampus

Glutamate neurotoxicity and diseases of the nervous system

▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

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Short-Term Synaptic Plasticity

The ionotropic glutamate receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding glutamate receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

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The glutamate receptor ion channels

The responses of vertebrate neurones to glutamate involve at least three receptor types. One of these, the NMDA receptor (so called because of its specific activation by N-methyl-D-aspartate), induces responses presenting a peculiar voltage sensitivity. Above resting potential, the current induced by a given dose of glutamate (or NMDA) increases when the cell is depolarized. This is contrary to what is observed at classical excitatory synapses, and recalls the properties of 'regenerative' systems like the Na+ conductance of the action potential. Indeed, recent studies of L-glutamate, L-aspartate and NMDA-induced currents have indicated that the current-voltage (I-V) relationship can show a region of 'negative conductance' and that the application of these agonists can lead to a regenerative depolarization. Furthermore, the NMDA response is greatly potentiated by reducing the extracellular Mg2+ concentration [( Mg2+]o) below the physiological level (approximately 1 mM). By analysing the responses of mouse central neurones to glutamate using the patch-clamp technique, we have now found a link between voltage sensitivity and Mg2+ sensitivity. In Mg2+-free solutions, L-glutamate, L-aspartate and NMDA open cation channels, the properties of which are voltage independent. In the presence of Mg2+, the single-channel currents measured at resting potential are chopped in bursts and the probability of opening of the channels is reduced. Both effects increase steeply with hyperpolarization, thereby accounting for the negative slope of the I-V relationship of the glutamate response. Thus, the voltage dependence of the NMDA receptor-linked conductance appears to be a consequence of the voltage dependence of the Mg2+ block and its interpretation does not require the implication of an intramembrane voltage-dependent 'gate'.

Magnesium gates glutamate-activated channels in mouse central neurones

Transmitters mediating 'fast' synaptic processes in the vertebrate central nervous system are commonly placed in two separate categories that are believed to exhibit no interaction at the receptor level. The 'inhibitory transmitters' (such as glycine and GABA) are considered to act only on receptors mediating a chloride conductance increase, whereas 'excitatory transmitters' (such as L-glutamate) are considered to activate receptors mediating a cationic conductance increase. The best known excitatory receptor is that specifically activated by N-methyl-D-aspartate (NMDA) which has recently been characterized at the single channel level. The response activated by NMDA agonists is unique in that it exhibits a voltage-dependent Mg block. We report here that this response exhibits another remarkable property: it is dramatically potentiated by glycine. This potentiation is not mediated by the inhibitory strychnine-sensitive glycine receptor, and is detected at a glycine concentration as low as 10 nM. The potentiation can be observed in outside-out patches as an increase in the frequency of opening of the channels activated by NMDA agonists. Thus, in addition to its role as an inhibitory transmitter, glycine may facilitate excitatory transmission in the brain through an allosteric activation of the NMDA receptor.

Glycine potentiates the NMDA response in cultured mouse brain neurons

1. Single-channel currents activated by N-methyl-D-aspartate (NMDA) agonists were analysed in the presence of various extracellular concentrations of divalent cations in outside-out patches from mouse neurones in primary culture. 2. In nominally Mg2+-free solutions the opening and closing of the channels leads to rectangular current pulses, the mean duration of which varies little with membrane potential. After addition of Mg2+, the single-channel currents recorded at negative potentials appear in bursts of short openings separated by brief closures. 3. The duration of the short openings decreases with increasing Mg2+ concentration, while the duration of the short closures is independent of the Mg2+ concentration. Depolarization increases the duration of the short openings and decreases the duration of the short closures. 4. The dependence of the burst structure on the Mg2+ concentration and on membrane potential is compatible to a first approximation with a model in which Mg2+ ions enter the open channel and block it by binding at a deep site. A better approximation requires, however, additional assumptions such as Mg2+ permeation and/or interactions between Ca2+ and Mg2+. 5. Increasing the extracellular Ca2+ concentration from 1 to 100 mM produces three effects on the currents flowing through NMDA channels. It shifts the reversal potential towards a positive value (+30 mV); it reduces the outward current flowing through the NMDA channels at very positive potentials; it reduces the inward current flowing at negative potentials. 6. The interpretation of the effects of Ca2+ appears to require three hypotheses: that Ca2+ permeates the NMDA channel, that there exists a significant surface potential at the entrance of the NMDA channel in physiological solutions and that both Ca2+ and monovalent cations bind to the channel, binding being stronger in the case of Ca2+ ions. 7. While Co2+ and, to a lesser extent, Mn2+ mimic the effects of Mg2+ on the NMDA channel, Ca2+, Ba2+ and Cd2+ do not. The distinction between Mg2+-like and Ca2+-like divalent cations corresponds to a difference in the speed of exchange of the water molecules surrounding the cations in solutions. Thus, it is possible that permeation occurs for all the divalent cations, but is slower for those which are slowly dehydrated.

The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture.

Micromolar concentrations of extracellular Zn2+ are known to antagonize native NMDA receptors via a dual mechanism involving both a voltage-independent and a voltage-dependent inhibition. We have tried to evaluate the relative importance of these two effects and their subunit specificity on recombinant NMDA receptors expressed in HEK 293 cells and Xenopus oocytes. The comparison of NR1a-NR2A and NR1a-NR2B receptors shows that the voltage-dependent inhibition is similar in both types of receptors but that the voltage-independent inhibition occurs at much lower Zn2+ concentrations in NR1a-NR2A receptors (IC50 in the nanomolar range) than in NR1a-NR2B receptors (IC50 in the micromolar range). The high affinity of the effect observed with NR1a-NR2A receptors was found to be attributable mostly to the slow dissociation of Zn2+ from its binding site. By analyzing the effects of Zn2+ on varied combinations of NR1 (NR1a or NR1b) and NR2 (NR2A, NR2B, NR2C), we show that both the NR1 and the NR2 subunits contribute to the voltage-independent Zn2+ inhibition. We have observed further that under control conditions, i.e., in zero nominal Zn2+ solutions, the addition of low concentrations of heavy metal chelators markedly potentiates the responses of NR1a-NR2A receptors, but not of NR1a-NR2B receptors. This result suggests that traces of a heavy metal (probably Zn2+) contaminate standard solutions and tonically inhibit NR1a-NR2A receptors. Chelation of a contaminant metal also could account for the rapid NR2A subunit-specific potentiations produced by reducing compounds like DTT or glutathione.

https://www.jneurosci.org/content/jneuro/17/15/5711.full.pdf

P Ascher

Papers

Magnesium gates glutamate-activated channels in mouse central neurones

Glycine potentiates the NMDA response in cultured mouse brain neurons

The role of divalent cations in the N-methyl-D-aspartate responses of mouse central neurones in culture.

High-Affinity Zinc Inhibition of NMDA NR1–NR2A Receptors

Electrophysiological studies of NMDA receptors