- Open Access
The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB
© Kandel; licensee BioMed Central Ltd. 2012
- Received: 22 February 2012
- Accepted: 18 April 2012
- Published: 14 May 2012
The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.
- Motor Neuron
- Sensory Neuron
- Synaptic Plasticity
- Classical Conditioning
- Synaptic Connection
By 1969, we had already learned from the pioneering work of Brenda Milner that certain forms of memory were stored in the hippocampus and the medial temporal lobe. In addition, the work of Larry Squire revealed that there are two major memory systems in the brain: explicit or declarative; implicit or procedural. Explicit memory, a memory for facts and events—for people, places, and objects—requires, as Milner has pointed out, the medial temporal lobe and the hippocampus[1–3]. By contrast, we knew less about the localization of implicit memory, a memory for perceptual and motor skills and other forms of procedural memory which proved to involve not one but a number of different brain systems: the cerebellum, the striatum, the amygdala, and in the most elementary instances, simple reflex pathways themselves. Moreover, we knew even less about the mechanisms of any form of memory storage. Indeed, we did not even know whether the storage mechanisms were synaptic or non-synaptic.
In 1968, Alden Spencer and I were invited to write a perspective of learning for Physiological Reviews, which we entitled “Cellular Neurophysiological Approaches in the Study of Learning.” In it we pointed out that there was no frame of reference for studying memory because one could not yet distinguish, experimentally, between the two conflicting approaches to the biology of memory that had been advanced up to that time: the aggregate field approach advocated by Karl Lashley in the 1950s and by Ross Adey in the 1960s, which assumed that information is stored in the bioelectric field generated by the aggregate activity of many neurons; and the cellular connectionist approach, which derived from Santiago Ramon y Cajal's idea which postulated that learning results from changes in the strength of the synapse. The cellular-connection idea was later renamed synaptic plasticity by Konorski in his 1948 book: Conditioned Reflexes and Neuronal Organization. Konorski’s idea was incorporated into a more specific model of certain types of learning by Hebb in 1949. Spencer and I concluded our review by emphasizing the need to develop tractable behavioral systems in which one could distinguish between these alternatives by relating, in a causal way, specific changes in the neuronal components of a behavior to modification of that behavior during learning and memory storage.
The first behavioral systems to be analyzed in this manner were simple forms of learning in the context of implicit memory. From 1964 to 1979, several useful model systems emerged: the flexion reflex of cats, the eye-blink response of rabbits, and a variety of simple forms of reflex learning in invertebrates: the gill-withdrawal reflex of Aplysia, olfactory learning in the fly, the escape reflex of Tritonia, and various behavioral modifications in Hermissenda, Pleurobranchaea, and Limax, crayfish, and honeybees. The studies were aimed at defining, then pinpointing, the neural circuits that mediate these behaviors and the critical synaptic sites within these circuits that are modified by learning and memory storage, and then specifying the cellular basis for those changes[7–14].
A number of insights rapidly emerged from this simple systems approach. The first was purely behavioral and revealed that even animals with a limited numbers of nerve cells—approximately 20,000 in the central nervous systems of Aplysia to 300,000 in Drosophila—have remarkable learning capabilities. In fact even the gill-withdrawal reflex, perhaps the simplest behavioral reflex of Aplysia, can be modified by five different forms of learning: habituation, dishabituation, sensitization, classical conditioning, and operant conditioning.
The availability of these simple systems opened up the first analyses of the mechanisms of memory, which focused initially on short-term changes lasting from a few minutes to an hour. These studies found that one mechanism for learning and short-term memory evident in both the gill-withdrawal reflex of Aplysia and in the tail flick response of crayfish is a change in synaptic strength brought about by modulating the release of transmitter. A decrease in transmitter release is associated with short-term habituation whereas an increase in transmitter release occurs during short-term dishabituation and sensitization ([16–20]; for early reviews, see[21, 22]).
Studies of memory in invertebrates also delineated a family of psychological concepts paralleling those first described in vertebrates by the classical behaviorists (Pavlov and Thorndike) and their modern counterparts (Kamin, Rescorla, and Wagner). These concepts include the distinction between various forms of associative and nonassociative learning and the insight that contingency – that the conditioned stimulus, in associative learning, is predictive of the unconditional stimulus - is more critical for learning than mere contiguity: the CS preceding the US (for review see). Here, for the first time, psychological concepts, which had been inferred from purely behavioral studies, could be explained in terms of their underlying cellular and molecular mechanisms. For example, the finding that the same sensory to motor neuron synapses that mediate the gill-withdrawal reflex are the cellular substrates of learning and memory illustrates that the storage of procedural memory does not depend on specialized, superimposed memory neurons whose only function is to store rather than process information. Rather, the capability for simple procedural memory storage is built into the neural architecture of the reflex pathway.
Retrograde signaling from the synapse to the nucleus
One of the features that fundamentally distinguishes the storage of long-term memory from short-term cellular changes is the requirement for the activation of gene expression. Given this requirement at the nucleus, one might expect that LTF would have to be cell-wide. However, experiments by Martin et al. using local applications of serotonin in the Aplysia bifurcated sensory neuron-two motor neuron culture preparation[63, 72], as well as parallel experiments by Frey and Morris in the hippocampus, demonstrated that synapses could be modified independently in a protein synthesis–dependent manner. Thus, LTF and the associated synaptic changes are synapse-specific, and this synapse specificity also requires CREB-1 and is blocked by an antibody to CREB-1. This implies that there must be not only retrograde signaling from the synapse back to the nucleus[72, 74], but also anterograde signaling from the nucleus to the synapse. Recently, Thompson et al. have found that serotonin stimulation which produces LTF in Aplysia sensory-motor neuron co-cultures triggers the nuclear translocation of importins, proteins involved in carrying cargos through nuclear pore complexes (see also). Similarly, in hippocampal neurons, NMDA activation or LTP induction, but not depolarization, leads to translocation of importin. Although details underlying the translocation of these retrograde signals remain unknown, the effector molecules identified thus far appear to be conserved in both invertebrates and vertebrates. The future identification of the molecular cargoes of importin and its signaling role in the nucleus are likely to increase our understanding of how transcription-dependent memory is regulated.
Following transcriptional activation, newly synthesized gene products, both mRNAs and proteins, have to be delivered specifically to the synapses whose activation originally triggered the wave of gene expression. To explain how this specificity can be achieved in a biologically economical way in spite of the massive number of synapses in a single neuron, Martin et al.[49, 61, 72] and Frey and Morris proposed the synaptic capture hypothesis. This hypothesis, also referred to some times as synaptic tagging, proposes that the products of gene expression are delivered throughout the cell, but are only functionally incorporated in those synapses that have been tagged by previous synaptic activity. The “synaptic tag” model has been supported by a number of studies both in the rodent hippocampus[73, 76–78] and Aplysia[63, 72].
Molecular mechanisms of synaptic capture
Studies of synaptic capture at the synapses between the sensory and motor neurons of the gill-withdrawal reflex in Aplysia have demonstrated that to achieve synapse-specific LTF more than the production of CRE-driven gene products in the nucleus is necessary. One also needs a PKA-mediated covalent signal to mark the stimulated synapses and local protein synthesis to stabilize that mark[63, 72]. Thus, injection into the cell body of phosphorylated CREB-1 gives rise to LTF at all the synapses of the sensory neuron by seeding these synapses with the protein products of CRE-driven genes. However, this facilitation is not maintained beyond 24–48 hours and not accompanied by synaptic growth unless the synapse is also marked by the short-term process, a single pulse of serotonin.
How is a synapse marked? Martin et al. found two distinct components of marking in Aplysia, one that requires PKA and initiates long-term synaptic plasticity and growth, and one that stabilizes long-term functional and structural changes at the synapse and requires (in addition to protein synthesis in the cell body) local protein synthesis at the synapse. Since mRNAs are made in the cell body, the need for the local translation of some mRNAs suggests that these mRNAs are presumably dormant while they are transported from the cell body to the synapses of the neuron and are only activated at appropriate synapses in response to specific signals. If that were true, one way of activating protein synthesis at these specific synapses would be to recruit to these synapses a regulator of translation that is capable of activating dormant mRNA.
Kausik Si began to search for such a regulator of protein synthesis. In Xenopus oocytes, Joel Richter had found that maternal RNA is silent until activated by the cytoplasmic polyadenylation element binding protein (CPEB). Si searched for a homolog in Aplysia and found in addition to the developmental isoform studied by Richter a new isoform of CPEB with novel properties. Blocking this isoform at a marked (active) synapse prevented the maintenance but not the initiation of long-term synaptic facilitation[80, 81]. Indeed, blocking ApCPEB blocks memory days after it is formed. An interesting feature about this isoform of Aplysia CPEB is that its N-terminus resembles the prion domain of yeast prion proteins and endows similar self-sustaining properties to Aplysia CPEB. But unlike other prions which are pathogenic, ApCPEB appears to be a functional prion. The active self-perpetuating form of the protein does not kill cells but rather has an important physiological function.
The Si lab and the Barry Dickson lab have found, independently, that long-term memory in Drosophila also involves CPEB for a learned courtship behavior in which males are conditioned to suppress their courtship upon prior exposure to unreceptive females. When the prion domain of the Drosophila CPEB is mutated, there is loss of long-term courtship memory[82, 83].
Prion-like proteins represent auto-replicative structures that may serve as a persistent form of information. Si and I have recently proposed a model based on the prion-like properties of Aplysia neuronal cytoplasmic polyadenylation element binding protein (CPEB). Neuronal CPEB can activate the translation of dormant mRNAs through the elongation of their poly-A tail. Aplysia CPEB has two conformational states: one is inactive or acts as a repressor, while the other is active. In a naive synapse, the basal level of CPEB expression is low and its state is inactive or repressive. According to the model of Si et al., serotonin induces an increase in the amount of neuronal CPEB. If a given threshold is reached, this causes the conversion of CPEB to the prion-like state, which is more active and lacks the inhibitory function of the basal state. Once the prion state is established at an activated synapse, dormant mRNAs, made in the cell body and distributed cell-wide, would be translated but only at the activated synapses. Because the activated CPEB can be self-perpetuating, it could contribute to a self-sustaining synapse-specific long-term molecular change and provide a mechanism for the stabilization of learning-related synaptic growth and the persistence of memory storage.
We now understand – in considerable molecular detail – the mechanisms underlying long-term learning-related synaptic plasticity, and the importance that such plastic changes play in memory storage, across a broad range of species and forms of memory. One surprising finding is the remarkable degree of conservation of the molecular memory mechanisms: cAMP, PKA, CRE, CREB-1 and CREB-2, and even CPEB, in different brain regions within a species and across species widely separated by evolution. In fact, one of the most striking features that has emerged through the application of molecular biology to neural science is the ability to see how unified all of the biological sciences have become.
However, although it is now clear that long-term synaptic plasticity is a key step in memory storage, it is important to note that a simple enhancement in the efficacy of a synapse is not sufficient to store a complex memory. Rather, changes in synaptic function must occur within the context of an ensemble of neurons to produce a specific alteration in information flow through a neural circuit. With the recent development of powerful genetic tools, it may soon be possible to meet the daunting challenge of visualizing and manipulating such changes in neural circuitry.
It also will be interesting to see to what degree computational models will contribute to our further understanding of synaptic plasticity. The influential cascade model of synaptically stored memory by Stefano Fusi, Patrick Drew, and Larry Abbott emphasizes that switch-like mechanisms are good for acquiring and storing memory but bad for retaining it. Retention, they argue, requires a cascade of states, each more stable than its precursor. As their hypothesis predicted, a progressive stabilization of changes in the synapse has been found to take place during the transition from short-term to intermediate-term to long-term memory storage (Jin et al.[122, 123]). Moreover, possible interactions between CPEB and PKC-ζ might provide additional semi-stable states within the long-term memory domain.
A major reason why computational neuroscience is rising and becoming more powerful and more interesting, as evident in the cascade model, is that these models lend themselves to experimental testing. In the future, however, computational models will need to broaden their focus to include the role of modulatory transmitters, the molecular components of synapses and their anatomical substrates.
Finally, we need to understand how memory is recalled. This is a deep problem whose analysis is just beginning. Mayford has made an important start of this problem and found that the same cells activated in the amygdala during the acquisition of learned fear are reactivated during retrieval of those memories. In fact, the number of reactivated neurons correlated positively with the behavioral expression of learned fear, indicating that associative memory has a stable neural correlate. But one of the characteristics of declarative memory is the requirement for conscious attention for recall. How does this attention mechanism come into play? Do modulatory transmitters such as dopamine and acetylcholine have a role in the retrieval process?
My research is supported by the Howard Hughes Medical Institute.
- Scoville WB, Milner B: Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psych. 1957, 20: 11-21. 10.1136/jnnp.20.1.11.Google Scholar
- Squire LR: Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans. Psychol Rev. 1992, 99: 195-231.PubMedGoogle Scholar
- Schacher DL, Tulving E: What are the memory systems of 1994?. memory systems. Edited by: Schacher DL, Tulving E. 1994, MIT Press, Cambridge, MA, 38-Google Scholar
- Kandel ER, Spencer WA: Cellular neurophysiological approaches in the study of learning. Physiol Rev. 1968, 48: 65-134.PubMedGoogle Scholar
- Cajal SR: La fine structure des centres nerveux. Proc R Soc Lond. 1894, 55: 444-468. 10.1098/rspl.1894.0063.Google Scholar
- Konorski J: Conditioned reflexes and neuronal organization. 1948, Cambridge University Press, New YorkGoogle Scholar
- Alkon DL: Associative training of Hermissenda. J Gen Physiol. 1974, 64: 70-84. 10.1085/jgp.64.1.70.PubMed CentralPubMedGoogle Scholar
- Dudai Y, Jan YN, Byers D, Quinn WG, Benzer S: Dunce, a mutant of Drosophila deficient in learning. Proc. Natl Acad Sci USA. 1976, 73: 1684-1688. 10.1073/pnas.73.5.1684.PubMed CentralPubMedGoogle Scholar
- Krasne FB: Excitation and habituation of the crayfish escape reflex: the depolarizing response in lateral giant fibres of the isolated abdomen. J Exp Biol. 1969, 50: 29-46.PubMedGoogle Scholar
- Kupfermann I, Kandel ER: Neuronal controls of a behavioral response mediated by the abdominal ganglion of Aplysia. Science. 1969, 164: 847-850. 10.1126/science.164.3881.847.PubMedGoogle Scholar
- Menzel R, Erber J: Learning and memory in bees. Sci Am. 1978, 239: 80-87.Google Scholar
- Quinn WG, Harris WA, Benzer S: Conditioned behavior in Drosophila melanogaster. Proc Natl Acad Sci USA. 1974, 71: 708-712. 10.1073/pnas.71.3.708.PubMed CentralPubMedGoogle Scholar
- Spencer W, Thompson RF, Nielson DR: Decrement of ventral root electrotonus and intracellularly recorded PSPs produced by iterated cutaneous afferent volleys. J Neurophysiol. 1966, 29: 253-274.PubMedGoogle Scholar
- Thompson RF, McCormick DA, Lavond DG, Clark GA, Kettner RE, Mauk MD: Initial localization of the memory trace for a basic form of associative learning. Prog Psychobiol Physiol Psychol. 1983, 10: 167-196.Google Scholar
- Kandel ER: The molecular biology of memory storage: A dialogue between genes and synapses. Science. 2001, 294: 1030-1038. 10.1126/science.1067020.PubMedGoogle Scholar
- Castellucci V, Pinsker H, Kupfermann I, Kandel ER: Neuronal mechanisms of habituation and dishabituation of the gill-withdrawal reflex in Aplysia. Science. 1970, 167: 1745-1748. 10.1126/science.167.3926.1745.PubMedGoogle Scholar
- Castellucci VF, Kandel ER, Schwartz JH, Wilson FD, Nairn AC, Greengard P: Intracellular injection of the catalytic subunit of cyclic AMP-dependent protein kinase simulates facilitation of transmitter release underlying behavioral sensitization in Aplysia. Proc Natl Acad Sci USA. 1980, 77: 7492-7496. 10.1073/pnas.77.12.7492.PubMed CentralPubMedGoogle Scholar
- Castellucci V, Kandel ER: Presynaptic facilitation as a mechanism for behavioral sensitization in Aplysia. Science. 1976, 194: 1176-1178. 10.1126/science.11560.PubMedGoogle Scholar
- Cohen RE, Kaplan SW, Kandel ER, Hawkins RD: A simplified preparation for relating cellular events to behavior: Mechanisms contributing to habituation, dishabituation, and sensitization of the Aplysia gill-withdrawal reflex. J Neurosci. 1997, 17: 2886-2899.PubMedGoogle Scholar
- Zucker RS, Kennedy D, Selverston AI: Neuronal circuit mediating escape responses in crayfish. Science. 1971, 173: 645-650. 10.1126/science.173.3997.645.PubMedGoogle Scholar
- Carew TJ, Sahley CJ: Invertebrate learning and memory: From behavior to molecules. Annu Rev Neurosci. 1986, 9: 435-487. 10.1146/annurev.ne.09.030186.002251.PubMedGoogle Scholar
- Kandel ER: Cellular basis of behavior: An introduction to behavioral neurobiology. 1976, W.H. Freeman, San FranciscoGoogle Scholar
- Rescorla RA, Wagner AR: A theory of Pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. Classical Conditioning II: Current Research and Theory. Edited by: Black AH, Prokasy WF. 1972, Appleton, New York, 64-99.Google Scholar
- Brunelli M, Castellucci V, Kandel ER: Synaptic facilitation and behavioral sensitization in Aplysia: Possible role of serotonin and cyclic AMP. Science. 1976, 194: 1178-1181. 10.1126/science.186870.PubMedGoogle Scholar
- Hawkins RD, Abrams TW, Carew TJ, Kandel ER: A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation. Science. 1983, 219: 400-415. 10.1126/science.6294833.PubMedGoogle Scholar
- Marinesco S, Carew TJ: Serotonin release evoked by tail nerve stimulation in the CNS of Aplysia: characterization and relationship to heterosynaptic plasticity. J Neurosci. 2002, 22: 2299-2312.PubMedGoogle Scholar
- Glanzman DL, Mackey SL, Hawkins RD, Dyke AM, Lloyd PE, Kandel ER: Depletion of serotonin in the nervous system of Aplysia reduces the behavioral enhancement of gill withdrawal as well as the heterosynaptic facilitation produced by tail shock. J Neurosci. 1989, 9: 4200-4213.PubMedGoogle Scholar
- Mackey SL, Kandel ER, Hawkins RD: Identified serotonergic neurons LCB1 and RCB1 in the cerebral ganglia of Aplysia produce presynaptic facilitation of siphon sensory neurons. J Neurosci. 1989, 9: 4227-4235.PubMedGoogle Scholar
- Sutherland EW: Studies on the mechanism of hormone action. Nobel Lectures in Physiology or Medicine (1971–1980). Edited by: Lindsten Jan. 1992, World Scientific Publishing Co, Singapore, 1-22.Google Scholar
- Corbin JD, Krebs EG: A cyclic AMP-stimulated protein kinase in adipose tissue. Biochem Biophys Res Comm. 1969, 36: 328-336. 10.1016/0006-291X(69)90334-9.PubMedGoogle Scholar
- Antonov I, Antonova I, Kandel ER, Hawkins RD: The contribution of activity-dependent synaptic plasticity to classical conditioning in Aplysia. J Neurosci. 2001, 21: 6413-6422.PubMedGoogle Scholar
- Lin XY, Glanzman DL: Hebbian induction of long-term potentiation of Aplysia sensorimotor synapses: partial requirement for activation of an NMDA-related receptor. Proc R Soc Lond B Biol Sci. 1994, 255: 215-221. 10.1098/rspb.1994.0031.Google Scholar
- Glanzman DL: Postsynaptic regulation of the development and long-term plasticity of Aplysia sensorimotor synapses in cell culture. J Neurobiol. 1994, 25: 666-693. 10.1002/neu.480250608.PubMedGoogle Scholar
- Antonov I, Antonova I, Kandel ER, Hawkins RD: Activity-dependent presynaptic facilitation and Hebbian LTP are both required and interact during classical conditioning in Aplysia. Neuron. 2003, 37: 135-147. 10.1016/S0896-6273(02)01129-7.PubMedGoogle Scholar
- Byrne JH, Kandel ER: Presynaptic facilitation revisited: state and time dependence. J Neurosci. 1996, 16: 425-435.PubMedGoogle Scholar
- Abrams TW, Karl KA, Kandel ER: Biochemical studies of a stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter. J Neurosci. 1991, 11: 2655-2665.PubMedGoogle Scholar
- Byers D, Davis RL, Kiger JA: Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster. Nature. 1981, 289: 79-81. 10.1038/289079a0.PubMedGoogle Scholar
- Carew TJ, Pinsker HM, Kandel ER: Long-term habituation of a defensive withdrawal reflex in Aplysia. Science. 1972, 175: 451-454. 10.1126/science.175.4020.451.PubMedGoogle Scholar
- Pinsker HM, Hening WA, Carew TJ, Kandel ER: Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science. 1973, 182: 1039-1042. 10.1126/science.182.4116.1039.PubMedGoogle Scholar
- Castellucci VF, Carew TJ, Kandel ER: Cellular analysis of long-term habituation of the gill-withdrawal reflex of Aplysia californica. Science. 1978, 202: 1306-1308. 10.1126/science.214854.PubMedGoogle Scholar
- Carew T, Castellucci VF, Kandel ER: Sensitization in Aplysia: restoration of transmission in synapses inactivated by long-term habituation. Science. 1979, 205: 417-419. 10.1126/science.451611.PubMedGoogle Scholar
- Dale N, Kandel ER: L-glutamate may be the fast excitatory transmitter of Aplysia sensory neurons. Proc Natl Acad Sci USA. 1993, 90: 7163-7167. 10.1073/pnas.90.15.7163.PubMed CentralPubMedGoogle Scholar
- Trudeau LE, Castellucci VF: Excitatory amino acid neurotransmission of sensory-motor and interneuronal synapses of Aplysia californica. J Neurophysiol. 1993, 70: 1221-1230.PubMedGoogle Scholar
- Montarolo PG, Goelet P, Castellucci VF, Morgan J, Kandel ER, Schacher S: A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science. 1986, 234: 1249-1254. 10.1126/science.3775383.PubMedGoogle Scholar
- Eliot LS, Hawkins RD, Kandel ER, Schacher S: Pairing-specific, activity-dependent presynaptic facilitation at Aplysia sensory-motor neuron synapses in isolated cell cultures. J Neurosci. 1994, 14: 368-383.PubMedGoogle Scholar
- Bao JX, Kandel ER, Hawkins RD: Involvement of presynaptic and postsynaptic mechanisms in a cellular analog of classical conditioning at Aplysia sensory-motor neuron synapse in isolated cell culture. J Neurosci. 1998, 18: 458-466.PubMedGoogle Scholar
- Schacher S, Wu F, Sun Z-Y: Pathway-specific synaptic plasticity: activity-dependent enhancement and suppression of long-term heterosynaptic facilitation at converging inputs on a single target. J Neurosci. 1997, 17: 597-606.PubMedGoogle Scholar
- Bacskai BJ, Hochner B, Mahaut-Smith M, Adams SR, Kaang BK, Kandel ER, Tsien RY: Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. Science. 1993, 260: 222-226. 10.1126/science.7682336.PubMedGoogle Scholar
- Martin KC, Michael D, Rose JC, Barad M, Casadio A, Zhu H, Kandel ER: MAP kinase translocates into the nucleus of the presynaptic cell and is required for long-term facilitation in Aplysia. Neuron. 1997, 18: 899-912. 10.1016/S0896-6273(00)80330-X.PubMedGoogle Scholar
- Sharma SK, Bagnall MW, Sutton MA, Carew TJ: Inhibition of calcineurin facilitates the induction of memory for sensitization in Aplysia: requirement of mitogen-activated protein kinase. Proc Natl Acad Sci USA. 2003, 100: 4861-4866. 10.1073/pnas.0830994100.PubMed CentralPubMedGoogle Scholar
- Montminy M: Transcriptional regulation by cyclic AMP. Annu Rev Biochem. 1997, 66: 807-822. 10.1146/annurev.biochem.66.1.807.PubMedGoogle Scholar
- Dash PK, Hochner B, Kandel ER: Injection of cAMP-responsive element into the nucleus of Aplysia sensory neurons blocks long-term facilitation. Nature. 1990, 345: 718-721. 10.1038/345718a0.PubMedGoogle Scholar
- Barco A, Pittenger C, Kandel ER: CREB, memory enhancement and the treatment of memory disorders: promises, pitfalls and prospects. Expert Opin Ther Targets. 2003, 7: 101-114. 10.1517/14728188.8.131.52.PubMedGoogle Scholar
- Lonze BE, Ginty DD: Function and regulation of CREB family transcription factors in the nervous system. Neuron. 2002, 35: 605-623. 10.1016/S0896-6273(02)00828-0.PubMedGoogle Scholar
- Hegde AN, Inokuchi K, Pei W, Casadio A, Ghirardi M, Chain DG, Martin KC, Kandel ER, Schwartz JH: Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. Cell. 1997, 89: 115-126. 10.1016/S0092-8674(00)80188-9.PubMedGoogle Scholar
- Alberini CM, Ghirardi M, Metz R, Kandel ER: C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in Aplysia. Cell. 1994, 76: 1099-1114. 10.1016/0092-8674(94)90386-7.PubMedGoogle Scholar
- Bartsch D, Ghirardi M, Casadio A, Giustetto M, Karl KA, Zhu H, Kandel ER: Enhancement of memory-related long-term facilitation by ApAF, a novel transcription factor that acts downstream from both CREB1 and CREB2. Cell. 2000, 103: 595-608. 10.1016/S0092-8674(00)00163-X.PubMedGoogle Scholar
- Abel T, Martin KC, Bartsch D, Kandel ER: Memory suppressor genes: Inhibitory constraints on the storage of long-term memory. Science. 1998, 279: 338-341. 10.1126/science.279.5349.338.PubMedGoogle Scholar
- Bartsch D, Ghirardi M, Skehel PA, Karl KA, Herder SP, Chen M, Bailey CH, Kandel ER: Aplysia CREB2 represses long-term facilitation: Relief of repression converts transient facilitation into long-term functional and structural change. Cell. 1995, 83: 979-992. 10.1016/0092-8674(95)90213-9.PubMedGoogle Scholar
- Guan Z, Kim JH, Lomvardas S, Holick K, Xu S, Kandel ER, Schwartz JH: p38 MAP kinase mediates both short-term and long-term synaptic depression in Aplysia. J Neurosci. 2003, 23: 7317-7325.PubMedGoogle Scholar
- Michael D, Martin KC, Seger R, Ning M-M, Baston R, Kandel ER: Repeated pulses of serotonin required for long-term facilitation activate mitogen-activated protein kinase in sensory neurons in Aplysia. Proc Natl Acad Sci USA. 1998, 95: 1864-1869. 10.1073/pnas.95.4.1864.PubMed CentralPubMedGoogle Scholar
- Bartsch D, Casadio A, Karl KA, Serodio P, Kandel ER: CREB1 encodes a nuclear activator, a repressor, and a cytoplasmic modulator that form a regulatory unit critical for long-term facilitation. Cell. 1998, 95: 211-223. 10.1016/S0092-8674(00)81752-3.PubMedGoogle Scholar
- Casadio A, Martin KC, Giustetto M, Zhu H, Chen M, Bartsch D, Bailey CH, Kandel ER: A transient, neuron-wide form of CREB-mediated long-term facilitation can be stabilized at specific synapses by local protein synthesis. Cell. 1999, 99: 221-237. 10.1016/S0092-8674(00)81653-0.PubMedGoogle Scholar
- Albensi BC, Mattson MP: Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000, 35: 151-159. 10.1002/(SICI)1098-2396(200002)35:2<151::AID-SYN8>3.0.CO;2-P.PubMedGoogle Scholar
- Izquierdo I, Cammarota M: Zif and the survival of memory. Science. 2004, 304: 829-830. 10.1126/science.1098139.PubMedGoogle Scholar
- Yin JCP, Wallach JHS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG, Tully T: Induction of a Dominant Negative CREB Transgene Specifically Blocks Long-Term Memory in Drosophila. Cell. 1994, 79: 49-58. 10.1016/0092-8674(94)90399-9.PubMedGoogle Scholar
- Waddell S, Quinn WG: Flies, genes, and learning. Annu Rev Neurosci. 2001, 24: 1283-1309. 10.1146/annurev.neuro.24.1.1283.PubMedGoogle Scholar
- Guan Z, Giustetto M, Lomvardas S, Kim JH, Miniaci MC, Schwartz JH, Thanos D, Kandel ER: Integration of long-term memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell. 2002, 111: 483-493. 10.1016/S0092-8674(02)01074-7.PubMedGoogle Scholar
- Levenson JM, Sweatt JD: Epigenetic mechanisms in memory formation. Nat Rev Neurosci. 2005, 6: 108-118. 10.1038/nrn1604. [Online]PubMedGoogle Scholar
- Hsieh J, Gage FH: Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol. 2005, 17: 664-671. 10.1016/j.ceb.2005.09.002.PubMedGoogle Scholar
- Bailey CH, Chen M: Long-term memory in Aplysia modulates the total number of varicosities of single identified sensory neurons. Proc Natl Acad Sci USA. 1988, 85: 2373-2377. 10.1073/pnas.85.7.2373.PubMed CentralPubMedGoogle Scholar
- Martin KC, Casadio A, Zhu H, Yaping E, Rose JC, Chen M, Bailey CH, Kandel ER: Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell. 1997, 91: 927-938. 10.1016/S0092-8674(00)80484-5.PubMedGoogle Scholar
- Frey U, Morris RG: Synaptic tagging and long-term potentiation. Nature. 1997, 385: 533-536. 10.1038/385533a0.PubMedGoogle Scholar
- Lee SH, Lim CS, Park H, Lee JA, Han JH, Kim H, Cheang YH, Lee SH, Lee YS, Ko HG, Jang DH, Kim H, Miniaci MC, Bartsch D, Kim E, Bailey CH, Kanel ER, Kaang BK: Nuclear translocation of CAM-associated protein activates transcription for long-term facilitation in Aplysia. Cell. 2007, 129 (4): 801-812. 10.1016/j.cell.2007.03.041.PubMedGoogle Scholar
- Thompson KR, Otis KO, Chen DY, Zhao Y, O’Dell TJ, Martin KC: Synapse to nucleus signaling during long-term synaptic plasticity: a role for the classical active nuclear import pathway. Neuron. 2004, 44: 997-1009.PubMedGoogle Scholar
- Barco A, Alarcon JM, Kandel ER: Expression of constitutively active CREB protein facilitates the late phase of long-term potentiation by enhancing synaptic capture. Cell. 2002, 108: 689-703. 10.1016/S0092-8674(02)00657-8.PubMedGoogle Scholar
- Dudek SM, Fields RD: Somatic action potentials are sufficient for late-phase LTP-related cell signaling. Proc Natl Acad Sci USA. 2002, 99: 3962-3967. 10.1073/pnas.062510599.PubMed CentralPubMedGoogle Scholar
- Frey U, Morris RG: Weak before strong: dissociating synaptic tagging and plasticity-factor accounts of late-LTP. Neuropharmacology. 1998, 37: 545-552. 10.1016/S0028-3908(98)00040-9.PubMedGoogle Scholar
- Richter JD: Cytoplasmic polyadenylation in development and beyond. Microbiol Mol Biol Rev. 1999, 63: 446-456.PubMed CentralPubMedGoogle Scholar
- Si K, Lindquist S, Kandel ER: A neuronal isoform of the Aplysia CPEB has prion-like properties. Cell. 2003, 115: 879-891. 10.1016/S0092-8674(03)01020-1.PubMedGoogle Scholar
- Si K, Giustetto M, Etkin A, Hsu R, Janisiewicz AM, Miniaci MC, Kim JH, Zhu H, Kandel ER: A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in Aplysia. Cell. 2003, 115: 893-904. 10.1016/S0092-8674(03)01021-3.PubMedGoogle Scholar
- Keleman K, Krüttner S, Alenius M, Dickson BJ: Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nat Neurosci. 2007, 10: 1587-1593. 10.1038/nn1996.PubMedGoogle Scholar
- Majumdar A, Cesario WC, White-Grindley E, Jiang H, Ren F, Khan MR, Li L, Choi EML, Kannan K, Guo F, Unruh J, Slaughter B, Si K: Ciritical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell. 2012, 148: 515-529. 10.1016/j.cell.2012.01.004.PubMedGoogle Scholar
- Tompa P, Friedrich P: Prion proteins as memory molecules: an hypothesis. Neuroscience. 1998, 86: 1037-1043.PubMedGoogle Scholar
- Si K, Choi Y-B, White-Grindley E, Majumdar A, Kandel ER: Aplysia CPEB can form prion-like multimers in sensory neurons that contribute to long-term facilitation. Cell. 2010, 140: 421-435. 10.1016/j.cell.2010.01.008.PubMedGoogle Scholar
- O'Keefe J, Nadel L: The Hippocampus as a Cognitive Map. 1978, The Clarendon Press, OxfordGoogle Scholar
- Bliss TV, Lomo T: Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973, 232: 331-356.PubMed CentralPubMedGoogle Scholar
- Bliss TV, Collingridge GL: A synaptic model of memory: Long-term potentiation in the hippocampus. Nature. 1993, 361: 31-39. 10.1038/361031a0.PubMedGoogle Scholar
- Watkins JC, Jane DE: The glutamate story. Brit J Pharmacol. 2006, 147: S100-S108.Google Scholar
- Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A: Magnesium gates glutamate-activated channels in mouse central neurones. Nature. 1984, 307: 462-465. 10.1038/307462a0.PubMedGoogle Scholar
- Westbrook G, Mayer M, Guthrie P: Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984, 309: 261-263. 10.1038/309261a0.PubMedGoogle Scholar
- Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F: Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature. 1983, 305: 719-721. 10.1038/305719a0.PubMedGoogle Scholar
- Malenka RC, Kauer JA, Zucker RS, Nicoll RA: Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. Science. 1988, 242: 81-84. 10.1126/science.2845577.PubMedGoogle Scholar
- Malenka RC, Kauer JA, Perkel DJ, Mauk MD, Kelly PT, Nicoll RA, Waxham MN: An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature. 1989, 340: 554-557. 10.1038/340554a0.PubMedGoogle Scholar
- Malinow R, Schulman H, Tsien RW: Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. Science. 1989, 245: 862-866. 10.1126/science.2549638.PubMedGoogle Scholar
- Malinow R, Madison DV, Tsien RW: Persistent protein kinase activity underlying long-term potentiation. Nature. 1988, 335: 820-824. 10.1038/335820a0.PubMedGoogle Scholar
- Grant SG, O’Dell TJ, Karl KA, Stein PL, Soriano P, Kandel ER: Impaired long-term potentiation, spatial learning, and hippocampal development in fyn mutant mice. Science. 1992, 258: 1903-1910. 10.1126/science.1361685.PubMedGoogle Scholar
- O'Dell TJ, Kandel ER, Grant SG: Long-term potentiation in the hippocampus is blocked by tyrosine kinase inhibitors. Nature. 1991, 353: 558-560. 10.1038/353558a0.PubMedGoogle Scholar
- Kauer JA, Malenka RC, Nicoll RA: A persistent postsynaptic modification mediates long-term potentiation in the hippocampus. Neuron. 1988, 10: 911-917.Google Scholar
- Shi SH, Hayashi Y, Petralia RS, Zaman SH, Wenthold RJ, Svoboda K, Malinow R: Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science. 1999, 284: 1811-1816. 10.1126/science.284.5421.1811.PubMedGoogle Scholar
- Carroll RC, Beattie EC, Xia H, Luscher C, Altschuler Y, Nicholl RA, Malenka RC, von Zastrow M: Proc Natl Acad Sci USA. 1999, 96: 14112-14117. 10.1073/pnas.96.24.14112.PubMed CentralPubMedGoogle Scholar
- Nicoll RA, Tomita S, Bredt D: Auxiliary subunits assist AMPA-type glutamate receptors. Science. 2006, 3: 1253-1256.Google Scholar
- Bolshakov VY, Siegelbaum S: Postsynaptic induction and presynaptic expression of hippocampal long-term depression. Science. 1994, 264: 1148-1152. 10.1126/science.7909958.PubMedGoogle Scholar
- Emptage NJ, Reid CA, Fine A, Bliss TV: Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses. Neuron. 2003, 38: 797-804. 10.1016/S0896-6273(03)00325-8.PubMedGoogle Scholar
- Reid CA, Dixon DB, Takahashi M, Bliss TV, Fine A: Optical quantal analysis indicates that long-term potentiation at single hippocampal mossy fiber synapses is expressed through increased release probability, recruitment of new release sites, and activation of silent synapses. J Neurosci. 2004, 24: 3618-3626. 10.1523/JNEUROSCI.3567-03.2004.PubMedGoogle Scholar
- Morris RGM: Long-term potentiation and memory. Philos Trans R Soc Lond B Biol Sci. 2003, 358: 643-647. 10.1098/rstb.2002.1230.PubMed CentralPubMedGoogle Scholar
- Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R: Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell. 1997, 88: 615-626. 10.1016/S0092-8674(00)81904-2.PubMedGoogle Scholar
- Frey U, Huang YY, Kandel ER: Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. Science. 1993, 260: 1661-1664. 10.1126/science.8389057.PubMedGoogle Scholar
- Bailey CH, Barco A, Hawkins RD, Kandel ER: Molecular studies of learning and memory in Aplysia and the hippocampus: a comparative analysis of implicit and explicit memory storage. Learning and memory: a comprehensive reference. Edited by: Byrne JH. 2008, Elsevier Press, Oxford, UK, 11-29.Google Scholar
- Capecchi MR: Gene Targeting 1977-Present. The Nobel Prizes. Edited by: Grandin Karl. 2008, The Nobel Foundation, Stockholm, 155-172.Google Scholar
- Smithies O: Turning Pages. The Nobel Prizes. Edited by: Karl Grandin. 2008, The Nobel Foundation, Stockholm, 209-230.Google Scholar
- Silva AJ, Paylor R, Wehner JM, Tonegawa S: Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992, 257: 206-211. 10.1126/science.1321493.PubMedGoogle Scholar
- Silva AJ, Stevens CF, Tonegawa S, Wang Y: Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science. 1992, 257: 201-206. 10.1126/science.1378648.PubMedGoogle Scholar
- Bourtchouladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ: Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell. 1994, 79: 59-68. 10.1016/0092-8674(94)90400-6.Google Scholar
- Pavlopoulos E, Trifillieff P, Chevaleyre V, Fioriti L, Zairis S, Pagano A, Malleret E, Kandel ER: Neuralized activates CPEB3: A function of nonproteolytic ubiquitin in synaptic plasticity and memory storage. Cell. 2011, 147: 1369-1383. 10.1016/j.cell.2011.09.056.PubMed CentralPubMedGoogle Scholar
- Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J, Alberini C, Kelley AE, Maren S, Rudy JW, Yin JC, Sacktor TC, Fenton AA: PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol. 2008, 6: 2698-2706.PubMedGoogle Scholar
- Han J-H, Kushner SA, Yiu AP, Cole CJ, Matynia A, Brown RA, Neve RL, Guzowski JF, Silva AJ, Josselyn SA: Neuronal competition and selection during memory formation. Science. 2007, 316: 457-460. 10.1126/science.1139438.PubMedGoogle Scholar
- Han J-H, Kushner SA, Yiu AP, Hsiang H-L, Buch T, Waisman A, Bontempi B, Neve RL, Frankland PW, Josselyn SA: Selective erasure of a fear memory. Science. 2009, 323: 1492-1496. 10.1126/science.1164139.PubMedGoogle Scholar
- Reijmers LG, Perkins BL, Matsuo NH, Mayford M: Localization of a Stable Neural Correlate of Associative Memory. Science. 2007, 317: 1230-1233. 10.1126/science.1143839.PubMedGoogle Scholar
- Arenkiel BR, Peca J, Davison IG, Feliciano C, Deisseroth K, Augustine GJ, Ehlers MD, Fang G: In vivo light-induced activation of neural circuitry in transgenic mice expressing channelrhodopsin-2. Neuron. 2007, 54: 205-218. 10.1016/j.neuron.2007.03.005.PubMed CentralPubMedGoogle Scholar
- Fusi S, Drew PJ, Abbott LF: Cascade models of synaptically stored memories. Neuron. 2005, 45: 599-611. 10.1016/j.neuron.2005.02.001.PubMedGoogle Scholar
- Jin I, Puthenveettil P, Udo H, Karl K, Kandel ER, Hawkins RD: Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation in Aplysia. Proc Natl Acad Sci. 2012, in pressGoogle Scholar
- Jin I, Udo H, Rayman JB, Puthenveettil S, Vishwasrao HD, Kandel ER, Hawkins RD: Postsynaptic mechanisms recruited by spontaneous transmitter release during long-term and intermediate-term facilitation in Aplysia. Proc Natl Acad Sci. 2012, in pressGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.