Long‐term Potentiation


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 (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.



Bliss TV and Collingridge GL (1993) A synaptic model of memory: long‐term potentiation in the hippocampus. Nature 361(6407): 31–39.

Bramham CR and Messaoudi E (2005) BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Progress in Neurobiology 76(2): 99–125.

Choi S, Klingauf J and Tsien RW (2003) Fusion pore modulation as a presynaptic mechanism contributing to expression of long‐term potentiation. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 358(1432): 695–705.

Connor JA, Miller LD, Petrozzino J and Muller W (1994) Calcium signaling in dendritic spines of hippocampal neurons. Journal of Neurobiology 25(3): 234–242.

El‐Husseini Ael D, Schnell E, Dakoji S et al. (2002) Synaptic strength regulated by palmitate cycling on PSD‐95. Cell 108(6): 849–863.

Frey U and Morris RG (1997) Synaptic tagging and long‐term potentiation. Nature 385(6616): 533–536.

Giese KP, Fedorov NB, Filipkowski RK and Silva AJ (1998) Autophosphorylation at Thr286 of the α calcium‐calmodulin kinase II in LTP and learning. Science 279(5352): 870–873.

Golding NL, Staff NP and Spruston N (2002) Dendritic spikes as a mechanism for cooperative long‐term potentiation. Nature 418(6895): 326–331.

Gruart A, Munoz MD and Delgado‐Garcia JM (2006) Involvement of the CA3‐CA1 synapse in the acquisition of associative learning in behaving mice. Journal of Neuroscience 26(4): 1077–1087.

Hardingham N and Fox K (2006) The role of nitric oxide and GluR1 in presynaptic and postsynaptic components of neocortical potentiation. Journal of Neuroscience 26(28): 7395–7404.

Harris KM, Fiala JC and Ostroff L (2003) Structural changes at dendritic spine synapses during long‐term potentiation. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 358(1432): 745–748.

Lee HK, Barbarosie M, Kameyama K, Bear MF and Huganir RL (2000) Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405(6789): 955–959.

Liao D, Hessler NA and Malinow R (1995) Activation of postsynaptically silent synapses during pairing‐induced LTP in CA1 region of hippocampal slice. Nature 375(6530): 400–404.

Lisman J (1989) A mechanism for the Hebb and the anti‐Hebb processes underlying learning and memory. Proceedings of the National Academy of Sciences of the USA 86(23): 9574–9578.

Lisman J (1994) The CaM kinase II hypothesis for the storage of synaptic memory. Trends Neuroscience 17(10): 406–412.

Lisman JE and Grace AA (2005) The hippocampal‐VTA loop: controlling the entry of information into long‐term memory. Neuron 46(5): 703–713.

Lisman J, Schulman H and Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nature Reviews Neuroscience 3(3): 175–190.

Lu FM and Hawkins RD (2006) Presynaptic and postsynaptic Ca(2+) and CamKII contribute to long‐term potentiation at synapses between individual CA3 neurons. Proceedings of the National Academy of Sciences of the USA 103(11): 4264–4269.

Lynch G, Larson J, Kelso S, Barrionuevo G and Schottler F (1983) Intracellular injections of EGTA block induction of hippocampal long‐term potentiation. Nature 305(5936): 719–721.

Malinow R and Malenka RC (2002) AMPA receptor trafficking and synaptic plasticity. Annual Review of Neuroscience 25: 103–126.

Matsuzaki M, Honkura N, Ellis‐Davies GC and Kasai H (2004) Structural basis of long‐term potentiation in single dendritic spines. Nature 429(6993): 761–766.

Morishita W, Marie H and Malenka RC (2005) Distinct triggering and expression mechanisms underlie LTD of AMPA and NMDA synaptic responses. Nature Neuroscience 8(8): 1043–1050.

Nicoll RA (2003) Expression mechanisms underlying long‐term potentiation: a postsynaptic view. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences 358(1432): 721–726.

Pastalkova E, Serrano P, Pinkhasova D et al. (2006) Storage of spatial information by the maintenance mechanism of LTP. Science 313(5790): 1141–1144.

Tsien JZ, Huerta PT and Tonegawa S (1996) The essential role of hippocampal CA1 NMDA receptor‐dependent synaptic plasticity in spatial memory. Cell 87(7): 1327–1338.

Tzingounis AV and Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52(3): 403–407.

Whitlock JR, Heynen AJ, Shuler MG and Bear MF (2006) Learning induces long‐term potentiation in the hippocampus. Science 313(5790): 1093–1097.

Zakharenko SS, Patterson SL, Dragatsis I et al. (2003) Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA1‐CA3 synapses. Neuron 39(6): 975–990.

Further Reading

Kelleher RJ 3rd, Govindarajan A and Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44(1): 59–73.

Malenka RC and Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44(1): 5–21.

Milner B, Squire LR and Kandel ER (1998) Cognitive neuroscience and the study of memory. Neuron 20: 445–468.

Roberson ED, English JD and Sweatt JD (1996) A biochemist's view of long‐term potentiation. Learning and Memory 3(1): 1–24.

Sheng M and Hoogenraad CC (2006) The postsynaptic architecture of excitatory synapses: a more quantitative view. Annual Review of Biochemistry 76 EPUB: http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.biochem.76.060805.160029

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

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