Graham L. Collingridge

NMDA receptors - their role in long-term potentiation

Abstract Long-term potentiation (LTP) has for a long time captured the imagination of neuroscientists as a model with which to probe the cellular mechanisms of learning and memory in the mammalian brain. In this article we describe the recent evidence that has revealed the pivotal role of NMDA receptors in the induction of LTP, and discuss the possible mechanisms involved in the maintenance of the potentiated state.

Excitatory amino acid receptors and synaptic plasticity

Excitatory amino acid receptors are the mediators of synaptic transmission at many synapses that can undergo use-dependent modifications of synaptic efficiency. They also play an essential role in the induction of these plastic changes. Graham Collingridge and Wolf Singer describe how NMDA receptors can endow synapses with hebbian-like properties and discuss how these may be used by vertebrates for associative learning and experience-dependent modifications of synaptic connections during development. The role of AMPA receptors in the maintenance of long-term potentiation is also discussed.

Receptor trafficking and synaptic plasticity

Long-term potentiation and long-term depression are processes that have been widely studied to understand the molecular basis of information storage in the brain. Glutamate receptors are required for the induction and expression of these forms of plasticity, and GABA (γ-aminobutyric acid) receptors are involved in their modulation. Recent insights into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for our understanding of the mechanisms of long-term potentiation and long-term depression.

Paired‐pulse depression of monosynaptic GABA‐mediated inhibitory postsynaptic responses in rat hippocampus.

1. Intracellular recording techniques were used to characterize monosynaptic inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) in rat hippocampal slices and to study the mechanism of paired‐pulse depression of these synaptic responses. This was achieved by stimulation in stratum radiatum close (less than 0.5 mm) to an intracellularly recorded CA1 neurone after pharmacological blockade of all excitatory synaptic transmission. 2. Under these conditions, low‐frequency stimulation (0.033 Hz) evoked a pure biphasic IPSP, which had a short and constant latency to onset. This IPSP was blocked by tetrodotoxin (1 microM) suggesting that it resulted from the electrical stimulation of the axons and/or cell bodies of a monosynaptic inhibitory pathway. 3. Picrotoxin (100 microM) abolished the early component of the biphasic IPSP/C. It left an intact, pure late IPSP/C (IPSP/CB) which had a latency to onset of 29 +/‐ 2 ms, latency to peak of 139 +/‐ 4 ms, a duration of 723 +/‐ 135 (range 390‐1730) ms and a reversal potential of ‐93 +/‐ 2 mV. The duration was highly dependent on the stimulus intensity whereas the latency to onset was largely independent of the stimulus intensity. The IPSP/CB was reduced or abolished by 1 mM‐phaclofen. 4. Phaclofen (1 mM) and 2‐hydroxy‐saclofen (0.1‐1.0 mM) reversibly depressed (60‐100%) the late component of the biphasic IPSP/C and, where maximally effective, left a pure, early IPSP/C (IPSP/CA). The IPSP/CA had a latency to onset of 3 ms or less, a latency to peak of 17 +/‐ 1 ms, a duration of 225 +/‐ 3 ms and a reversal potential of ‐75 +/‐ 2 mV. 5. Two shocks of identical strength were applied in close succession to characterize, and to study the mechanisms underlying, frequency‐dependent depression of inhibitory synaptic responses. Paired‐pulse depression was seen for both phases of the biphasic IPSP/C and of the pure IPSP/CB, recorded in the presence of picrotoxin. Paired‐pulse depression was not accompanied by changes in the reversal potential of either component, indicating that it was caused by a reduction in the two synaptic conductances. Paired‐pulse depression was greater when high stimulus intensities were employed. 6. Paired stimuli were applied at separation intervals of between 5 ms and 10 s to determine the temporal profile of frequency‐dependent depression. Paired‐pulse depression of both IPSCA and IPSCB was most pronounced at an interstimulus interval of 100‐125 ms and ceased to occur at intervals greater than 5 10s.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential Roles of NR2A and NR2B-Containing NMDA Receptors in Cortical Long-Term Potentiation and Long-Term Depression

It is widely believed that long-term depression (LTD) and its counterpart, long-term potentiation (LTP), involve mechanisms that are crucial for learning and memory. However, LTD is difficult to induce in adult cortex for reasons that are not known. Here we show that LTD can be readily induced in adult cortex by the activation of NMDA receptors (NMDARs), after inhibition of glutamate uptake. Interestingly there is no need to activate synaptic NMDARs to induce this LTD, suggesting that LTD is triggered primarily by extrasynaptic NMDA receptors. We also find that de novo LTD requires the activation of NR2B-containing NMDAR, whereas LTP requires activation of NR2A-containing NMDARs. Surprisingly another form of LTD, depotentiation, requires activation of NR2A-containing NMDARs. Therefore, NMDARs with different synaptic locations and subunit compositions are involved in various forms of synaptic plasticity in adult cortex.

NSF Binding to GluR2 Regulates Synaptic Transmission

Here, we show that N-ethylmaleimide-sensitive fusion protein (NSF) interacts directly and selectively with the intracellular C-terminal domain of the GluR2 subunit of AMPA receptors. The interaction requires all three domains of NSF but occurs between residues Lys-844 and Gln-853 of rat GluR2, with Asn-851 playing a critical role. Loading of decapeptides corresponding to the NSF-binding domain of GluR2 into rat hippocampal CA1 pyramidal neurons results in a marked, progressive decrement of AMPA receptor-mediated synaptic transmission. This reduction in synaptic transmission was also observed when an anti-NSF monoclonal antibody (mAb) was loaded into CA1 neurons. These results demonstrate a previously unsuspected direct interaction in the postsynaptic neuron between two major proteins involved in synaptic transmission and suggest a rapid NSF-dependent modulation of AMPA receptor function.

Long-term depression in the CNS

Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.

Modulation of AMPA receptor unitary conductance by synaptic activity

Activity-dependent alteration in synaptic strength is a fundamental property of the vertebrate central nervous system and is thought to underlie learning and memory. The most extensively studied model of activity-dependent synaptic plasticity is long-term potentiation (LTP) of glutamate-responsive (glutamatergic) synapses, a widespread phenomenon involving multiple mechanisms. The best characterized form of LTP occurs in the CA1 region of the hippocampus, in which LTP is initiated by transient activation of NMDA (N-methyl-D-aspartate) receptors and is expressed as a persistent increase in synaptic transmission through AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate) receptors. This increase is due, at least in part, to a postsynaptic modification of AMPA-receptor function; this modification could be caused by an increase in the number of receptors, their open probability, their kinetics or their single-channel conductance. Here we show that the induction of LTP in the CA1 region of the hippocampus is often associated with an increase in single-channel conductance of AMPA receptors. This shows that elementary channel properties can be rapidly modified by synaptic activity and provides an insight into one molecular mechanism by which glutamatergic synapses can alter their strength.

Memories of NMDA receptors and LTP

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A nomenclature for ligand-gated ion channels

The ligand-gated ion channels that participate in fast synaptic transmission comprise the nicotinic acetylcholine, 5-hydroxytryptamine3 (5-HT3), gamma-aminobutyric acidA (GABA(A)), glycine, ionotropic glutamate and P2X receptor families. A consistent and systematic nomenclature for the individual subunits that comprise these receptors and the receptors that result from their co-assembly is highly desirable. There is also a need to develop criteria that aid in deciding which of the vast number of heteromeric combinations of subunits that can be assembled in heterologous expression systems in vitro, are known, or likely, to exist as functional receptors in vivo. The aim of this short article is to summarize the progress being made by the nomenclature committee of IUPHAR (NC-IUPHAR) in formulating recommendations that attempt to address these issues.