- 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.
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