Review
LTP mechanisms: from silence to four-lane traffic

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Abstract

Brief periods of strong neuronal activity induce long-lasting changes in synaptic function. This synaptic plasticity is thought to play important roles in learning and memory. One example — long-term potentation in the CA1 region of the hippocampus — has been studied extensively, and conflicting views regarding the underlying mechanisms have emerged. Recent findings, regarding basic properties of synaptic transmission, appear to reconcile these diverging views.

Introduction

There has been much interest in delineating the mechanisms underlying long-term potentiation (LTP). A detailed understanding of LTP may allow us to determine its roles in learning and memory and developmental plasticity. Mechanistic studies over the last three decades have produced contradictory models regarding the synaptic sites that undergo modification during LTP. However, work over the last few years has led to a model that includes delivery of receptors to functional ‘silent’ synapses. This model can account for most results in this field. Here, we review the evidence supporting this model and extend the model to include more recent results on receptor trafficking.

Section snippets

Why study long-term potentiation?

For almost 30 years there has been considerable effort by a number of laboratories to determine if the modification underlying long-term potentiation (LTP) takes place pre- or postsynaptically (reviewed in 1, 2, 3). This issue is important for several reasons. First, once the site of the modification that is responsible for LTP is found, it should be easier to identify the relevant cellular and molecular machinery. Such identification could facilitate determining the relationship between LTP

Mechanistic studies

The initial steps that trigger LTP have long been agreed on. Evoking synaptic transmission at a low frequency activates primarily AMPA-type glutamate receptors and leads to a small rise in intracellular calcium concentration. Intense synaptic activity that triggers LTP activates NMDA receptors and produces a significant rise in the postsynaptic calcium concentration. Events downstream of this are progressively less well understood. The activation of the calcium/calmodulin-dependent protein

Silent synapses: biophysical basis

A postsynaptic mechanism for LTP was proposed a decade ago, based on two observations: first, LTP selectively increases the postsynaptic current that is attributable to AMPA receptor channels 6, 7; second, LTP can increase the sensitivity to exogenously delivered AMPA [8]. This view was seriously challenged a few years later by studies showing that the frequency of failures in synaptic transmission (a classic measure of presynaptic function) changes during LTP 9, 10, 11, 12, 13, 14, 15. This

Silent synapses: role in LTP

The discovery and general acceptance of silent synapses has had two important consequences for LTP research. The first of these consequences is that their presence provides critical evidence for a purely postsynaptic mechanism for LTP that can explain a wide range of previous physiological observations 3, 36. In this model (see Figure 1), LTP results from the delivery of functional AMPA receptors to synapses from non-synaptic sites. These sites could be either intracellular, or on nearby

Focus on AMPA receptors

The second, and arguably more significant, fallout of the exciting discovery of silent synapses is that it has moved the field of LTP research beyond the general pre- versus post-synaptic dichotomy and focused attention on a much more specific molecular question: how are functional AMPA receptors added to synapses? Our understanding of the cellular and molecular mechanisms controlling the organization of these receptors is rapidly expanding. The AMPA receptor is a heteromeric complex made up of

AMPA receptor traffic

How do the molecular interactions between AMPA receptors and their associated proteins regulate synaptic plasticity and stability? Our current understanding is still murky, but a number of recent studies provide interesting clues. NSF is a protein involved in the presynaptic fusion machinery that is also present in postsynaptic sites and interacts with GluR2 54•, 55•, 57•, 61•. Expression of a peptide that interferes with the interaction of NSF and GluR2 causes a decrease in surface AMPA

Trafficking model for plasticity

The dichotomy between the properties of GluR1/4 and GluR2/3 subunits, with respect to carboxy-tails, interaction proteins, and apparent roles in basal transmission and plasticity, leads us to suggest a model for subunit-specific trafficking of AMPA receptors that can account for a wide range of experimental observations regarding LTP. The basic principle of our model is that two distinct regulatory mechanisms govern the local insertion and removal of AMPA receptors from the synapse: a

Conclusion

In the future, we expect that there will be much work examining in detail how signal transduction mechanisms interact with the machinery that regulates the trafficking of AMPA receptors and their associated proteins. This should lead to an elucidation of the roadways used to achieve ‘AMPA-fication’, and ultimately a satisfactory molecular understanding of LTP.

Acknowledgements

We thank S Shi, J Esteban, J Zhu, A Piccini, A Barria and F Kamenetz for helpful discussions.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (68)

  • R.C. Malenka et al.

    Silent synapses speak up

    Neuron

    (1997)
  • C. Luscher et al.

    Monitoring glutamate release during LTP with glial transporter currents

    Neuron

    (1998)
  • J.S. Diamond et al.

    Glutamate release monitored with astrocyte transporter currents during LTP

    Neuron

    (1998)
  • T.A. Ryan et al.

    Potentiation of evoked vesicle turnover at individually resolved synaptic boutons

    Neuron

    (1996)
  • J.H. Kim et al.

    Organization and regulation of proteins at synapses

    Curr Opin Cell Biol

    (1999)
  • A. Nishimune et al.

    NSF binding to GluR2 regulates synaptic transmission

    Neuron

    (1998)
  • I. Song et al.

    Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors

    Neuron

    (1998)
  • J. Xia et al.

    Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1

    Neuron

    (1999)
  • P. Osten et al.

    The AMPA receptor GluR2 C terminus can mediate a reversible, ATP-dependent interaction with NSF and alpha- and beta-SNAPs

    Neuron

    (1998)
  • S. Srivastava et al.

    Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP

    Neuron

    (1998)
  • H. Inagaki et al.

    rDLG6: a novel homolog of drosophila DLG expressed in rat brain

    Biochem Biophys Res Commun

    (1999)
  • A.S. Leonard et al.

    SAP97 is associated with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit

    J Biol Chem

    (1998)
  • C. Luscher et al.

    Role of AMPA receptor cycling in synaptic transmission and plasticity

    Neuron

    (1999)
  • J. Noel et al.

    Surface expression of AMPA receptors in hippocampal neurons is regulated by an NSF-dependent mechanism

    Neuron

    (1999)
  • A. Luthi et al.

    Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction

    Neuron

    (1999)
  • Z. Jia et al.

    Enhanced LTP in mice deficient in the AMPA receptor GluR2

    Neuron

    (1996)
  • R.A. Nicoll et al.

    Contrasting properties of two forms of long-term potentiation in the hippocampus

    Nature

    (1995)
  • R. Malinow

    LTP: desperately seeking resolution

    Science

    (1994)
  • L.F. Abbott et al.

    Synaptic depression and cortical gain control

    Science

    (1997)
  • D. Muller et al.

    Contributions of quisqualate and NMDA receptors to the induction and expression of LTP

    Science

    (1988)
  • S.N. Davies et al.

    Temporally distinct pre- and post-synaptic mechanisms maintain long-term potentiation

    Nature

    (1989)
  • R. Malinow et al.

    Presynaptic enhancement shown by whole-cell recordings of long-term potentiation in hippocampal slices

    Nature

    (1990)
  • D.M. Kullmann et al.

    Long-term potentiation is associated with increases in quantal content and quantal amplitude

    Nature

    (1992)
  • A. Larkman et al.

    Presynaptic release probability influences the locus of long-term potentiation

    Nature

    (1992)
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