Trends in Neurosciences
ReviewLTP forms 1, 2 and 3: different mechanisms for the ‘long’ in long-term potentiation
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.
References (89)
- et al.
Synaptic plasticity: hippocampal LTP
Curr. Opin. Neurobiol.
(1995) - et al.
LTP and LTD: an embarrassment of riches
Neuron
(2004) - et al.
Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases
Prog. Neurobiol.
(2003) Long-term potentiation phenomena in the rat limbic forebrain
Brain Res.
(1983)Ca2+ and synaptic plasticity
Cell Calcium
(2005)- et al.
Thapsigargin blocks long-term potentiation induced by weak, but not strong tetanisation in rat hippocampal CA1 neurons
Neurosci. Lett.
(1995) Local calcium signaling in neurons
Neuron
(2003)Homer regulates gain of ryanodine receptor type 1 channel complex
J. Biol. Chem.
(2002)Metabotropic glutamate receptors: electrophysiological properties and role in plasticity
Brain Res. Brain Res. Rev.
(1999)Synergistic release of Ca2+ from IP3-sensitive stores evoked by synaptic activation of mGluRs paired with backpropagating action potentials
Neuron
(1999)
Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation
Curr. Opin. Neurobiol.
ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors
Neuron
Involvement of multiple phosphatidylinositol 3-kinase-dependent pathways in the persistence of late-phase long term potentiation expression
Neuroscience
The phosphoinositide 3-kinase and p70 S6 kinase regulate long-term potentiation in hippocampal neurons
Neuroscience
Translational regulatory mechanisms in persistent forms of synaptic plasticity
Neuron
Maintenance of long-term potentiation in rat dentate gyrus requires protein synthesis but not messenger RNA synthesis immediately post-tetanization
Neuroscience
Kinase suppressor of Ras1 compartmentalizes hippocampal signal transduction and subserves synaptic plasticity and memory formation
Neuron
Disruption of dendritic translation of CaMKIIα impairs stabilization of synaptic plasticity and memory consolidation
Neuron
Regulation of gene expression by Ca2+ signals in neuronal cells
Eur. J. Pharmacol.
Temporal integration of intracellular Ca2+ signaling networks in regulating gene expression by action potentials
Cell Calcium
Induction of CRE-mediated gene expression by stimuli that generate long-lasting LTP in area CA1 of the hippocampus
Neuron
Dopamine: a potential substrate for synaptic plasticity and memory mechanisms
Prog. Neurobiol.
CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events
Neuron
Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1–CA3 synapses
Neuron
NMDA receptors and voltage-dependent calcium channels mediate different aspects of acquisition and retention of a spatial memory task
Neurobiol. Learn. Mem.
Hippocampus-dependent memory formation: do memory type-specific mechanisms exist?
J Pharmacol. Sci.
Facilitation of NMDAR-independent LTP and spatial learning in mutant mice lacking ryanodine receptor type 3
Neuron
Stable hippocampal long-term potentiation elicited by ‘theta’ pattern stimulation
Brain Res.
Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation
Brain Res.
Long-term potentiation and memory
Physiol. Rev.
Synaptic plasticity at hippocampal mossy fibre synapses
Nat. Rev. Neurosci.
Multiple, developmentally regulated expression mechanisms of long-term potentiation at CA1 synapses
J. Neurosci.
A developmental switch in the signaling cascades for LTP induction
Nat. Neurosci.
Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path
J. Physiol.
How long will long-term potentiation last?
Philos. Trans. R. Soc. Lond. B Biol. Sci.
Macromolecules and the maintenance of long-term potentiation
Two components of long-term potentiation induced by different patterns of afferent activation
Nature
VDCCs and NMDARs underlie two forms of LTP in CA1 hippocampus in vivo
J. Neurophysiol.
Electrical stimuli patterned after the theta-rhythm induce multiple forms of LTP
J. Neurophysiol.
Different calcium sources are narrowly tuned to the induction of different forms of LTP
J. Neurophysiol.
Spatial segregation of neuronal calcium signals encodes different forms of LTP in rat hippocampus
J. Physiol.
N-methyl-d-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons
Proc. Natl. Acad. Sci. U. S. A.
Differential immunohistochemical localization of inositol 1,4,5-trisphosphate- and ryanodine-sensitive Ca2+ release channels in rat brain
J. Neurosci.
Clustering of L-type Ca2+ channels at the base of major dendrites in hippocampal pyramidal neurons
Nature
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