Review
LTP forms 1, 2 and 3: different mechanisms for the ‘long’ in long-term potentiation

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Long-term potentiation (LTP) of synaptic transmission is a primary experimental model of memory formation in neuronal circuits. Because of the intellectual appeal and scientific fecundity of the field, it is perhaps unsurprising that the literature on LTP contains many complex and often contradictory findings. Recognition that LTP is not a unitary phenomenon and mechanisms can differ between brain regions has resolved some controversy. However, further categorization can be made of mechanistically discrete forms of LTP at the same set of synapses. LTP1, LTP2 and LTP3 have previously been defined according to differences in the longevity and general molecular mechanisms of LTP. This review aims to reinvigorate and extend this concept as a useful framework to disentangle the mechanisms of LTP.

Introduction

While LTP was regarded as a unitary phenomenon, the means used to produce it could be regarded as irrelevant, so long as an end result was achieved. As we become aware of the diversity of pathways and related changes that can be called into play under different circumstances, the details of the experimental conditions become vitally important’ [1].

Clearly, more than a decade ago it was already apparent that some of the disparity in the literature on long-term potentiation (LTP) could be explained by the existence of multiple LTP mechanisms. Today, it is clear that LTP [and long-term depression (LTD)] can involve different mechanisms, depending on the cell type, development stage and induction protocol 2, 3. Thus, in addition to the classical postsynaptically-induced, NMDA receptor-dependent form of LTP described at the CA3–CA1 synapse in the hippocampus, there are also presynaptic, NMDA receptor-independent forms, such as at the neighboring dentate gyrus (DG)–CA3 mossy fiber synapse [4]. In CA1, LTP can be expressed as an increase in neurotransmitter release and/or postsynaptic responsiveness to glutamate, depending on the age of the animal [5]. The sensitivity of LTP in CA1 to different kinase inhibitors is also developmentally regulated [6]. However, it is less well recognized that multiple, mechanistically distinct forms of LTP remain if the cell type, age and other experimental conditions are constant.

Section snippets

Early and late long-term potentiation versus long-term potentiation forms 1, 2 and 3

In the original description of LTP in the DG of the hippocampus, it was observed that repeated delivery of conditioning stimuli resulted in synaptic potentiation of greater magnitude and persistence [7]. Although initially attributed to the addition of nonsaturated expression mechanisms, it soon became clear that multiple repetitions of a specific induction paradigm (Box 1) recruits a protein synthesis-dependent component to LTP 8, 9. This form of LTP [late (L)-LTP] is long-lasting (hours in

Different induction mechanisms for long-term potentiation

LTP (all forms) in the hippocampus is commonly induced by ‘tetanic’ or high-frequency electrical stimulation (HFS) of presynaptic axons (Box 1). Such stimulation results in a pattern of glutamate release that is sufficient to activate postsynaptic NMDA receptors. It is clear that postsynaptic Ca2+ influx is essential for induction of LTP and that Ca2+-permeable NMDA receptors have a central role in the DG and CA1 2, 12. However, neurons possess several alternative sources of Ca2+ that are also

Different effector mechanisms for long-term potentiation

If spatially discrete Ca2+ signals trigger forms of LTP with different durations, it stands to reason that the downstream mechanisms are also, at least partially, different. At first glance, a sensible categorization of the biochemical processes underlying LTP would seem improbable. However, three broad mechanisms have emerged that seem to encompass most of the recent data: post-translational modification (primarily phosphorylation), dendritic protein synthesis and nuclear gene transcription.

Different long-term potentiation expression mechanisms?

It seems there has always been a debate regarding the nature and locus of the changes that directly underlie increased synaptic efficacy. Possibilities include a presynaptic enhancement of neurotransmitter release or an increase in the number and/or function of postsynaptic receptors, or both. There is evidence to suggest that different expression mechanisms are associated with different forms of LTP. A general trend in expression studies is that longer-lasting forms of LTP, induced by strong

Concluding remarks

Recent findings support and extend the mechanistic dissociation of at least three different forms of LTP at synapses in the DG and CA1 of the hippocampus. The current LTP1, LTP2 and LTP3 model (Figure 2) describes LTP type-specific pathways that incorporate preferred or selective links between particular induction, signal transduction and effector systems. The activation of a specific pathway determines the longevity of the resultant LTP. LTP1, LTP2 and LTP3 could be activated independently,

Acknowledgements

The author is particularly indebted to Steve Redman for supporting his research and providing valuable discussion. Thanks also go to John Bekkers for his critical appraisal of the manuscript.

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