Long-term potentiation: outstanding questions and attempted synthesis

Lisman, John

doi:10.1098/rstb.2002.1242

Cited by 240Neuroscience and Neuropharmacology ResearchMemory and Neural MechanismsNeural dynamics and brain function

Long-term potentiation: outstanding questions and attempted synthesis

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Lisman, John·2003·Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences

DOI 10.1098/rstb.2002.1242PMC PMC1693147

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Abstract

This article attempts an overview of the mechanism of NMDAR-dependent long-term potentiation (LTP) and its role in hippocampal networks. Efforts are made to integrate information, often in speculative ways, and to identify unresolved issues about the induction, expression and molecular storage processes. The pre/post debate about LTP expression has been particularly difficult to resolve. The following hypothesis attempts to reconcile the available physiological evidence as well as anatomical evidence that LTP increases synapse size. It is proposed that synapses are composed of a variable number of trans-synaptic modules, each having presynaptic release sites and a postsynaptic structure that can be AMPAfied by the addition of a hyperslot assembly that anchors 10-20 AMPA channels. According to a newly developed view of transmission, the quantal response is generated by AMPA channels near the site of vesicle release and so will depend on whether the module where release occurs has been AMPAfied. LTP expression may involve two structurally mediated processes: (i) the AMPAfication of existing modules by addition of hyperslot assemblies: this is a purely postsynaptic process and produces an increase in the probability of an AMPA response, with no change in the NMDA component; and (ii) the addition of new modules: this is a structurally coordinated pre/post process that leads to LTP-induced synapse enlargement and potentiation of the NMDA component owing to an increase in the number of release sites (the number of NMDA channels is assumed to be fixed). The protocol used for LTP induction appears to affect the proportion of these two processes; pairing protocols that involve low-frequency presynaptic stimulation induce only AMPAfication, making LTP purely postsynaptic, whereas high-frequency stimulation evokes both processes, giving rise to a presynaptic component. This model is capable of reconciling much of the seemingly contradictory evidence in the pre/post debate. The structural nature of the postulated changes is relevant to a second debate: whether a CaMKII switch or protein-dependent structural change is the molecular memory mechanism. A possible reconciliation is that a reversible CaMKII switch controls the construction of modules and hyperslot assemblies from newly synthesized proteins.

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Authors: Lisman, J.
Affiliations: Department of Biology and Volen Center for Complex Systems, MS 008, 415 South Street, Waltham, MA 02454, USA ()
Corresponding author: Lisman, John
ORCID: Lisman, John
Venue: Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences
Publisher: The Royal Society
Published: 2003-04-29
Volume: 358
Issue: 1432
Pages: 829-842
ISSN: 0962-8436 (ISSN-L)
1471-2970
DOI: 10.1098/rstb.2002.1242
PMC: PMC1693147
OpenAlex: W2124812605
Cited by: 240
References: 105
Citations by year: 2026: 3 · 2025: 2 · 2024: 8 · 2023: 3 · 2022: 1 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 11 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 18 · 2012: 12
FWCI: 1.97
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: royalsociety.org/journals/ethics-policies/data-sharing-mining/ (tdm)
Locations: Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5r01ns035083-04)
National Institute of Neurological Disorders and Stroke (R01NS027337, R01 NS27337, R01 NS35083)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords: long-term potentiation, NMDA receptor, AMPA receptors, synaptic plasticity, hippocampus, presynaptic release sites, CaMKII, molecular memory, synaptic transmission
MeSH terms: Animals, Calcium, Chemoreceptor Cells, Hippocampus, Memory, Models, Neurological, Nerve Tissue Proteins, Synapses, Long-Term Potentiation, Calcium-Calmodulin-Dependent Protein Kinases, Calcium-Calmodulin-Dependent Protein Kinase Type 2

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Long-term potentiation: outstanding questions and attempted synthesis

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