Search tips
Search criteria 


Logo of transbThe Royal Society PublishingPhilosophical Transactions BAboutBrowse By SubjectAlertsFree Trial
Philos Trans R Soc Lond B Biol Sci. 2003 April 29; 358(1432): 829–842.
PMCID: PMC1693147

Long-term potentiation: outstanding questions and attempted synthesis.


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.

Full Text

The Full Text of this article is available as a PDF (379K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Asztely Fredrik, Wigström Holger, Gustafsson Bengt. The Relative Contribution of NMDA Receptor Channels in the Expression of Long-term Potentiation in the Hippocampal CA1 Region. Eur J Neurosci. 1992;4(8):681–690. [PubMed]
  • Barco Angel, Alarcon Juan M, Kandel Eric R. Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 2002 Mar 8;108(5):689–703. [PubMed]
  • Barria A, Muller D, Derkach V, Griffith LC, Soderling TR. Regulatory phosphorylation of AMPA-type glutamate receptors by CaM-KII during long-term potentiation. Science. 1997 Jun 27;276(5321):2042–2045. [PubMed]
  • Bashir ZI, Alford S, Davies SN, Randall AD, Collingridge GL. Long-term potentiation of NMDA receptor-mediated synaptic transmission in the hippocampus. Nature. 1991 Jan 10;349(6305):156–158. [PubMed]
  • Bayer KU, De Koninck P, Leonard AS, Hell JW, Schulman H. Interaction with the NMDA receptor locks CaMKII in an active conformation. Nature. 2001 Jun 14;411(6839):801–805. [PubMed]
  • Benke TA, Lüthi A, Isaac JT, Collingridge GL. Modulation of AMPA receptor unitary conductance by synaptic activity. Nature. 1998 Jun 25;393(6687):793–797. [PubMed]
  • Bolshakov VY, Golan H, Kandel ER, Siegelbaum SA. Recruitment of new sites of synaptic transmission during the cAMP-dependent late phase of LTP at CA3-CA1 synapses in the hippocampus. Neuron. 1997 Sep;19(3):635–651. [PubMed]
  • Bortolotto ZA, Bashir ZI, Davies CH, Collingridge GL. A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation. Nature. 1994 Apr 21;368(6473):740–743. [PubMed]
  • Bozdagi O, Shan W, Tanaka H, Benson DL, Huntley GW. Increasing numbers of synaptic puncta during late-phase LTP: N-cadherin is synthesized, recruited to synaptic sites, and required for potentiation. Neuron. 2000 Oct;28(1):245–259. [PubMed]
  • Brown GP, Blitzer RD, Connor JH, Wong T, Shenolikar S, Iyengar R, Landau EM. Long-term potentiation induced by theta frequency stimulation is regulated by a protein phosphatase-1-operated gate. J Neurosci. 2000 Nov 1;20(21):7880–7887. [PubMed]
  • Buchs PA, Muller D. Induction of long-term potentiation is associated with major ultrastructural changes of activated synapses. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):8040–8045. [PubMed]
  • Burgin KE, Waxham MN, Rickling S, Westgate SA, Mobley WC, Kelly PT. In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. J Neurosci. 1990 Jun;10(6):1788–1798. [PubMed]
  • Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS, Nicoll RA. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature. 2000 Dec 21;408(6815):936–943. [PubMed]
  • Chetkovich DM, Sweatt JD. nMDA receptor activation increases cyclic AMP in area CA1 of the hippocampus via calcium/calmodulin stimulation of adenylyl cyclase. J Neurochem. 1993 Nov;61(5):1933–1942. [PubMed]
  • Choi S, Klingauf J, Tsien RW. Postfusional regulation of cleft glutamate concentration during LTP at 'silent synapses'. Nat Neurosci. 2000 Apr;3(4):330–336. [PubMed]
  • Daw Michael I, Bortolotto Zuner A, Saulle Emilia, Zaman Shahid, Collingridge Graham L, Isaac John T R. Phosphatidylinositol 3 kinase regulates synapse specificity of hippocampal long-term depression. Nat Neurosci. 2002 Sep;5(9):835–836. [PubMed]
  • Diamond JS, Jahr CE. Asynchronous release of synaptic vesicles determines the time course of the AMPA receptor-mediated EPSC. Neuron. 1995 Nov;15(5):1097–1107. [PubMed]
  • El-Husseini AE, Schnell E, Chetkovich DM, Nicoll RA, Bredt DS. PSD-95 involvement in maturation of excitatory synapses. Science. 2000 Nov 17;290(5495):1364–1368. [PubMed]
  • El-Husseini Alaa El-Din, Schnell Eric, Dakoji Srikanth, Sweeney Neal, Zhou Qiang, Prange Oliver, Gauthier-Campbell Catherine, Aguilera-Moreno Andrea, Nicoll Roger A, Bredt David S. Synaptic strength regulated by palmitate cycling on PSD-95. Cell. 2002 Mar 22;108(6):849–863. [PubMed]
  • Engert F, Bonhoeffer T. Dendritic spine changes associated with hippocampal long-term synaptic plasticity. Nature. 1999 May 6;399(6731):66–70. [PubMed]
  • Fortin Norbert J, Agster Kara L, Eichenbaum Howard B. Critical role of the hippocampus in memory for sequences of events. Nat Neurosci. 2002 May;5(5):458–462. [PubMed]
  • Foster TC, McNaughton BL. Long-term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content. Hippocampus. 1991 Jan;1(1):79–91. [PubMed]
  • Frey U, Morris RG. Synaptic tagging and long-term potentiation. Nature. 1997 Feb 6;385(6616):533–536. [PubMed]
  • Frey U, Morris RG. Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology. 1998 Apr-May;37(4-5):545–552. [PubMed]
  • Frey U, Krug M, Reymann KG, Matthies H. Anisomycin, an inhibitor of protein synthesis, blocks late phases of LTP phenomena in the hippocampal CA1 region in vitro. Brain Res. 1988 Jun 14;452(1-2):57–65. [PubMed]
  • Frey U, Schollmeier K, Reymann KG, Seidenbecher T. Asymptotic hippocampal long-term potentiation in rats does not preclude additional potentiation at later phases. Neuroscience. 1995 Aug;67(4):799–807. [PubMed]
  • Fukunaga K, Stoppini L, Miyamoto E, Muller D. Long-term potentiation is associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem. 1993 Apr 15;268(11):7863–7867. [PubMed]
  • Gardoni F, Caputi A, Cimino M, Pastorino L, Cattabeni F, Di Luca M. Calcium/calmodulin-dependent protein kinase II is associated with NR2A/B subunits of NMDA receptor in postsynaptic densities. J Neurochem. 1998 Oct;71(4):1733–1741. [PubMed]
  • Gasparini S, Saviane C, Voronin LL, Cherubini E. Silent synapses in the developing hippocampus: lack of functional AMPA receptors or low probability of glutamate release? Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9741–9746. [PubMed]
  • Geinisman Y, Detoledo-Morrell L, Morrell F, Heller RE. Hippocampal markers of age-related memory dysfunction: behavioral, electrophysiological and morphological perspectives. Prog Neurobiol. 1995 Feb;45(3):223–252. [PubMed]
  • Genoux David, Haditsch Ursula, Knobloch Marlen, Michalon Aubin, Storm Daniel, Mansuy Isabelle M. Protein phosphatase 1 is a molecular constraint on learning and memory. Nature. 2002 Aug 29;418(6901):970–975. [PubMed]
  • Giese KP, Fedorov NB, Filipkowski RK, Silva AJ. Autophosphorylation at Thr286 of the alpha calcium-calmodulin kinase II in LTP and learning. Science. 1998 Feb 6;279(5352):870–873. [PubMed]
  • Hanson PI, Meyer T, Stryer L, Schulman H. Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron. 1994 May;12(5):943–956. [PubMed]
  • Harris KM, Jensen FE, Tsao B. Three-dimensional structure of dendritic spines and synapses in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of synaptic physiology and long-term potentiation. J Neurosci. 1992 Jul;12(7):2685–2705. [PubMed]
  • Hayashi Y, Shi SH, Esteban JA, Piccini A, Poncer JC, Malinow R. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science. 2000 Mar 24;287(5461):2262–2267. [PubMed]
  • Hoffman DA, Sprengel R, Sakmann B. Molecular dissection of hippocampal theta-burst pairing potentiation. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7740–7745. [PubMed]
  • Huang Yi-Shuian, Jung Mi-Young, Sarkissian Madathia, Richter Joel D. N-methyl-D-aspartate receptor signaling results in Aurora kinase-catalyzed CPEB phosphorylation and alpha CaMKII mRNA polyadenylation at synapses. EMBO J. 2002 May 1;21(9):2139–2148. [PubMed]
  • Jensen O, Lisman JE. Hippocampal CA3 region predicts memory sequences: accounting for the phase precession of place cells. Learn Mem. 1996 Sep-Oct;3(2-3):279–287. [PubMed]
  • Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001 Nov 2;294(5544):1030–1038. [PubMed]
  • Krucker Thomas, Siggins George R, McNamara Robert K, Lindsley Kristen A, Dao Alan, Allison David W, De Lecea Luis, Lovenberg Timothy W, Sutcliffe J Gregor, Gerendasy Dan D. Targeted disruption of RC3 reveals a calmodulin-based mechanism for regulating metaplasticity in the hippocampus. J Neurosci. 2002 Jul 1;22(13):5525–5535. [PubMed]
  • Kuhnt U, Hess G, Voronin LL. Statistical analysis of long-term potentiation of large excitatory postsynaptic potentials recorded in guinea pig hippocampal slices: binomial model. Exp Brain Res. 1992;89(2):265–274. [PubMed]
  • Kullmann DM. Amplitude fluctuations of dual-component EPSCs in hippocampal pyramidal cells: implications for long-term potentiation. Neuron. 1994 May;12(5):1111–1120. [PubMed]
  • Kullmann DM, Nicoll RA. Long-term potentiation is associated with increases in quantal content and quantal amplitude. Nature. 1992 May 21;357(6375):240–244. [PubMed]
  • Kullmann DM, Erdemli G, Asztély F. LTP of AMPA and NMDA receptor-mediated signals: evidence for presynaptic expression and extrasynaptic glutamate spill-over. Neuron. 1996 Sep;17(3):461–474. [PubMed]
  • Larkman A, Stratford K, Jack J. Quantal analysis of excitatory synaptic action and depression in hippocampal slices. Nature. 1991 Mar 28;350(6316):344–347. [PubMed]
  • Larkman AU, Jack JJ, Stratford KJ. Quantal analysis of excitatory synapses in rat hippocampal CA1 in vitro during low-frequency depression. J Physiol. 1997 Dec 1;505(Pt 2):457–471. [PubMed]
  • Lee HK, Barbarosie M, Kameyama K, Bear MF, Huganir RL. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature. 2000 Jun 22;405(6789):955–959. [PubMed]
  • Liao D, Jones A, Malinow R. Direct measurement of quantal changes underlying long-term potentiation in CA1 hippocampus. Neuron. 1992 Dec;9(6):1089–1097. [PubMed]
  • Ling Douglas S F, Benardo Larry S, Serrano Peter A, Blace Nancy, Kelly Matthew T, Crary John F, Sacktor Todd C. Protein kinase Mzeta is necessary and sufficient for LTP maintenance. Nat Neurosci. 2002 Apr;5(4):295–296. [PubMed]
  • Lisman JE. Relating hippocampal circuitry to function: recall of memory sequences by reciprocal dentate-CA3 interactions. Neuron. 1999 Feb;22(2):233–242. [PubMed]
  • Lisman J, Schulman H, Cline H. The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci. 2002 Mar;3(3):175–190. [PubMed]
  • Lisman JE, Harris KM. Quantal analysis and synaptic anatomy--integrating two views of hippocampal plasticity. Trends Neurosci. 1993 Apr;16(4):141–147. [PubMed]
  • Lisman JE, Zhabotinsky AM. A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron. 2001 Aug 2;31(2):191–201. [PubMed]
  • Liu G, Choi S, Tsien RW. Variability of neurotransmitter concentration and nonsaturation of postsynaptic AMPA receptors at synapses in hippocampal cultures and slices. Neuron. 1999 Feb;22(2):395–409. [PubMed]
  • Ma L, Zablow L, Kandel ER, Siegelbaum SA. Cyclic AMP induces functional presynaptic boutons in hippocampal CA3-CA1 neuronal cultures. Nat Neurosci. 1999 Jan;2(1):24–30. [PubMed]
  • McAllister AK, Stevens CF. Nonsaturation of AMPA and NMDA receptors at hippocampal synapses. Proc Natl Acad Sci U S A. 2000 May 23;97(11):6173–6178. [PubMed]
  • Magee JC, Cook EP. Somatic EPSP amplitude is independent of synapse location in hippocampal pyramidal neurons. Nat Neurosci. 2000 Sep;3(9):895–903. [PubMed]
  • Makhinson M, Chotiner JK, Watson JB, O'Dell TJ. Adenylyl cyclase activation modulates activity-dependent changes in synaptic strength and Ca2+/calmodulin-dependent kinase II autophosphorylation. J Neurosci. 1999 Apr 1;19(7):2500–2510. [PubMed]
  • Malinow R. Transmission between pairs of hippocampal slice neurons: quantal levels, oscillations, and LTP. Science. 1991 May 3;252(5006):722–724. [PubMed]
  • Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci. 2001 Nov;4(11):1086–1092. [PubMed]
  • Miller SG, Kennedy MB. Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell. 1986 Mar 28;44(6):861–870. [PubMed]
  • Montgomery Johanna M, Madison Daniel V. State-dependent heterogeneity in synaptic depression between pyramidal cell pairs. Neuron. 2002 Feb 28;33(5):765–777. [PubMed]
  • Montgomery JM, Pavlidis P, Madison DV. Pair recordings reveal all-silent synaptic connections and the postsynaptic expression of long-term potentiation. Neuron. 2001 Mar;29(3):691–701. [PubMed]
  • Nádasdy Z, Hirase H, Czurkó A, Csicsvari J, Buzsáki G. Replay and time compression of recurring spike sequences in the hippocampus. J Neurosci. 1999 Nov 1;19(21):9497–9507. [PubMed]
  • Nakazawa Kazu, Quirk Michael C, Chitwood Raymond A, Watanabe Masahiko, Yeckel Mark F, Sun Linus D, Kato Akira, Carr Candice A, Johnston Daniel, Wilson Matthew A, et al. Requirement for hippocampal CA3 NMDA receptors in associative memory recall. Science. 2002 Jul 12;297(5579):211–218. [PMC free article] [PubMed]
  • Nusser Z, Lujan R, Laube G, Roberts JD, Molnar E, Somogyi P. Cell type and pathway dependence of synaptic AMPA receptor number and variability in the hippocampus. Neuron. 1998 Sep;21(3):545–559. [PubMed]
  • O'Keefe J, Recce ML. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus. 1993 Jul;3(3):317–330. [PubMed]
  • Ostroff Linnaea E, Fiala John C, Allwardt Brenda, Harris Kristen M. Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices. Neuron. 2002 Aug 1;35(3):535–545. [PubMed]
  • Otmakhov N, Griffith LC, Lisman JE. Postsynaptic inhibitors of calcium/calmodulin-dependent protein kinase type II block induction but not maintenance of pairing-induced long-term potentiation. J Neurosci. 1997 Jul 15;17(14):5357–5365. [PubMed]
  • Ouyang Y, Rosenstein A, Kreiman G, Schuman EM, Kennedy MB. Tetanic stimulation leads to increased accumulation of Ca(2+)/calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons. J Neurosci. 1999 Sep 15;19(18):7823–7833. [PubMed]
  • Passafaro M, Piëch V, Sheng M. Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons. Nat Neurosci. 2001 Sep;4(9):917–926. [PubMed]
  • Petersen CC, Malenka RC, Nicoll RA, Hopfield JJ. All-or-none potentiation at CA3-CA1 synapses. Proc Natl Acad Sci U S A. 1998 Apr 14;95(8):4732–4737. [PubMed]
  • Petralia RS, Esteban JA, Wang YX, Partridge JG, Zhao HM, Wenthold RJ, Malinow R. Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses. Nat Neurosci. 1999 Jan;2(1):31–36. [PubMed]
  • Poncer Jean Christophe, Esteban Jose A, Malinow Roberto. Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II. J Neurosci. 2002 Jun 1;22(11):4406–4411. [PubMed]
  • Racca C, Stephenson FA, Streit P, Roberts JD, Somogyi P. NMDA receptor content of synapses in stratum radiatum of the hippocampal CA1 area. J Neurosci. 2000 Apr 1;20(7):2512–2522. [PubMed]
  • Renger JJ, Egles C, Liu G. A developmental switch in neurotransmitter flux enhances synaptic efficacy by affecting AMPA receptor activation. Neuron. 2001 Feb;29(2):469–484. [PubMed]
  • Sanna Pietro Paolo, Cammalleri Maurizio, Berton Fulvia, Simpson Cindy, Lutjens Robert, Bloom Floyd E, Francesconi Walter. Phosphatidylinositol 3-kinase is required for the expression but not for the induction or the maintenance of long-term potentiation in the hippocampal CA1 region. J Neurosci. 2002 May 1;22(9):3359–3365. [PubMed]
  • Selig DK, Hjelmstad GO, Herron C, Nicoll RA, Malenka RC. Independent mechanisms for long-term depression of AMPA and NMDA responses. Neuron. 1995 Aug;15(2):417–426. [PubMed]
  • Shen K, Teruel MN, Connor JH, Shenolikar S, Meyer T. Molecular memory by reversible translocation of calcium/calmodulin-dependent protein kinase II. Nat Neurosci. 2000 Sep;3(9):881–886. [PubMed]
  • Shi S, Hayashi Y, Esteban JA, Malinow R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell. 2001 May 4;105(3):331–343. [PubMed]
  • Skaggs WE, McNaughton BL. Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience. Science. 1996 Mar 29;271(5257):1870–1873. [PubMed]
  • Skaggs WE, McNaughton BL, Wilson MA, Barnes CA. Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences. Hippocampus. 1996;6(2):149–172. [PubMed]
  • Strack S, Barban MA, Wadzinski BE, Colbran RJ. Differential inactivation of postsynaptic density-associated and soluble Ca2+/calmodulin-dependent protein kinase II by protein phosphatases 1 and 2A. J Neurochem. 1997 May;68(5):2119–2128. [PubMed]
  • Stricker C, Field AC, Redman SJ. Changes in quantal parameters of EPSCs in rat CA1 neurones in vitro after the induction of long-term potentiation. J Physiol. 1996 Jan 15;490(Pt 2):443–454. [PubMed]
  • Stricker C, Field AC, Redman SJ. Statistical analysis of amplitude fluctuations in EPSCs evoked in rat CA1 pyramidal neurones in vitro. J Physiol. 1996 Jan 15;490(Pt 2):419–441. [PubMed]
  • Takumi Y, Ramírez-León V, Laake P, Rinvik E, Ottersen OP. Different modes of expression of AMPA and NMDA receptors in hippocampal synapses. Nat Neurosci. 1999 Jul;2(7):618–624. [PubMed]
  • Tsodyks MV, Skaggs WE, Sejnowski TJ, McNaughton BL. Population dynamics and theta rhythm phase precession of hippocampal place cell firing: a spiking neuron model. Hippocampus. 1996;6(3):271–280. [PubMed]
  • Walikonis RS, Oguni A, Khorosheva EM, Jeng CJ, Asuncion FJ, Kennedy MB. Densin-180 forms a ternary complex with the (alpha)-subunit of Ca2+/calmodulin-dependent protein kinase II and (alpha)-actinin. J Neurosci. 2001 Jan 15;21(2):423–433. [PubMed]
  • Weeks Andrew C W, Ivanco Tammy L, Leboutillier Janelle C, Marrone Diano F, Racine Ronald J, Petit Ted L. Unique changes in synaptic morphology following tetanization under pharmacological blockade. Synapse. 2003 Jan;47(1):77–86. [PubMed]
  • Wittenberg Gayle M, Tsien Joe Z. An emerging molecular and cellular framework for memory processing by the hippocampus. Trends Neurosci. 2002 Oct;25(10):501–505. [PubMed]
  • Wong ST, Athos J, Figueroa XA, Pineda VV, Schaefer ML, Chavkin CC, Muglia LJ, Storm DR. Calcium-stimulated adenylyl cyclase activity is critical for hippocampus-dependent long-term memory and late phase LTP. Neuron. 1999 Aug;23(4):787–798. [PubMed]
  • Xie X, Berger TW, Barrionuevo G. Isolated NMDA receptor-mediated synaptic responses express both LTP and LTD. J Neurophysiol. 1992 Apr;67(4):1009–1013. [PubMed]
  • Zhu J Julius, Qin Yi, Zhao Mingming, Van Aelst Linda, Malinow Roberto. Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell. 2002 Aug 23;110(4):443–455. [PubMed]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society