Long‐term Potentiation

Abstract

Long‐term potentiation is an activity‐dependent strengthening of synapses that is thought to underlie memory.

Keywords: long‐term potentiation; synaptic plasticity; learning; memory

Figure 1.

Postsynaptic mechanisms underlying long‐term potentiation (LTP), long‐term depression (LTD) and depotentiation (adapted from (Lisman, )). A dendritic spine is shown protruding from a small region of dendrite. The synaptic transmission (far right) is mediated by the neurotransmitter glutamate. The postsynaptic membrane contains AMPA and NMDA ionotropic glutamate channels and the metabotropic glutamate receptor, mGluR5. If the postsynaptic cell is strongly depolarized and if glutamate is being released presynaptically, then the NMDA receptor channel will open and LTP will be induced. The NMDA receptor channel itself is under complex control through positive and negative feedback loops. The final consequence of NMDA receptor channel opening is a high elevation of intracellular Ca+, which then triggers processes that lead to the upregulation of AMPA receptor channels. The upregulation occurs either by phosphorylation of existing AMPA receptor channels or by addition of new channels (see bottom of figure). During LTP induction the activity of CaM‐kinase is enhanced and this produces the phosphorylation of AMPA receptor channels. CaM‐kinase itself becomes phosphorylated and in this state, its phosphorylation is self‐sustaining. Other protein kinases, PKA and PKC may also be involved in the phosphorylation of AMPA receptor channels. The controls on PKC appear to be complex and involve the synthesis of new forms (PKM‐ζ) and the control by a positive feedback pathway involving arachidonic acid (AA), phospholipase A2 and RAS. The addition of new AMPA receptor channels depends on the movement of vesicles containing AMPA receptor channels into the spine during LTP induction and the fusion of vesicles containing AMPA receptor channels into the plasma membrane. Fusion involves two proteins, SNAP and NSF. The Ca2+ elevation that occurs during synaptic signalling may also depend on Ca2+ released from intracellular stores by IP3 receptors and ryanodine receptors and by Ca2+ entry through l‐type voltage‐dependent Ca2+ channels located in the spines. If postsynaptic depolarization is not strong, NMDA receptor channels will be only moderately activated and this will lead to a moderate elevation of Ca2+ that induces synaptic weakening (LTD or depotentiation). One form of this weakening is controlled by activation of a phosphatase pathway involving phosphatase 2B (pp2b), which dephosphorylates Inhibitor 1 (I1), and leads to activation of phosphatase 1 (PP1). One role of PP1 is to dephosphorylate CaMK and this may lead to synaptic weakening. During LTP induction, when it is important for CaMK to become phosphorylated, it is undesirable to activate PP1. This is prevented by a pathway involving adenylate cyclase 1 (AC1), cAMP and PKA. This pathway acts to counteract the effect of pp2b on I1. Other molecules of potential significance for LTP include the cell adhesion factors shown on the bottom right and the activity‐dependent mechanism that controls the translation of CaMK mRNA.

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Further Reading

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Lisman, John(Sep 2007) Long‐term Potentiation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000165.pub2]