The Molecular Biology of Memory: Camp, PKA, CRE, CREB-1, CREB-2, and CPEB Eric R Kandel
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Kandel Molecular Brain 2012, 5:14 http://www.molecularbrain.com/content/5/1/14 REVIEW Open Access The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB Eric R Kandel Abstract 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. Background: Simple systems in the study of memory that had been advanced up to that time: the of implicit learning and memory aggregate field approach advocated by Karl Lashley in By 1969, we had already learned from the pioneering the 1950s and by Ross Adey in the 1960s, which work of Brenda Milner that certain forms of memory assumed that information is stored in the bioelectric field were stored in the hippocampus and the medial temporal generated by the aggregate activity of many neurons; lobe. In addition, the work of Larry Squire revealed that and the cellular connectionist approach, which derived there are two major memory systems in the brain: explicit from Santiago Ramon y Cajal's idea [5] which postulated or declarative; implicit or procedural. Explicit memory, a that learning results from changes in the strength of the memory for facts and events—for people, places, and synapse. The cellular-connection idea was later renamed objects—requires, as Milner has pointed out, the medial synaptic plasticity by Konorski in his 1948 book: Condi- temporal lobe and the hippocampus [1-3]. By contrast, tioned Reflexes and Neuronal Organization [6]. Konors- we knew less about the localization of implicit memory, a ki’s idea was incorporated into a more specific model memory for perceptual and motor skills and other forms of certain types of learning by Hebb in 1949. Spencer of procedural memory which proved to involve not one and I concluded our review by emphasizing the need to but a number of different brain systems: the cerebellum, develop tractable behavioral systems in which one could the striatum, the amygdala, and in the most elementary distinguish between these alternatives by relating, in a instances, simple reflex pathways themselves. Moreover, causal way, specific changes in the neuronal components we knew even less about the mechanisms of any form of of a behavior to modification of that behavior during memory storage. Indeed, we did not even know whether learning and memory storage [4]. the storage mechanisms were synaptic or non-synaptic. The first behavioral systems to be analyzed in this In 1968, Alden Spencer and I were invited to write a manner were simple forms of learning in the context of perspective of learning for Physiological Reviews, which implicit memory. From 1964 to 1979, several useful we entitled “Cellular Neurophysiological Approaches in model systems emerged: the flexion reflex of cats, the the Study of Learning.” [4] In it we pointed out that eye-blink response of rabbits, and a variety of simple forms there was no frame of reference for studying memory of reflex learning in invertebrates: the gill-withdrawal because one could not yet distinguish, experimentally, reflex of Aplysia, olfactory learning in the fly, the es- between the two conflicting approaches to the biology cape reflex of Tritonia, and various behavioral modifi- cations in Hermissenda, Pleurobranchaea, and Limax, crayfish, and honeybees. The studies were aimed at defi- Correspondence: [email protected] Department of Neuroscience, Columbia University, 1051 Riverside Drive, ning, then pinpointing, the neural circuits that mediate #664, New York, NY 10032, USA these behaviors and the critical synaptic sites within these © 2012 Kandel; licensee 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. Kandel Molecular Brain 2012, 5:14 Page 2 of 12 http://www.molecularbrain.com/content/5/1/14 circuits that are modified by learning and memory sto- reflex in Aplysia revealed a biochemical mechanism for rage, and then specifying the cellular basis for those the short-term increase in transmitter release produced changes [7-14]. by sensitization [24] and later for classical conditioning A number of insights rapidly emerged from this simple (Hawkins et al., [25]). A single noxious (sensitizing) systems approach. The first was purely behavioral and stimulus to the tail of Aplysia leads to the activation of revealed that even animals with a limited numbers of three known classes of modulatory neurons, the most nerve cells—approximately 20,000 in the central nervous important of which uses the modulatory transmitter systems of Aplysia to 300,000 in Drosophila—have serotonin [26-28]. Serotonin stimulates the increase in remarkable learning capabilities. In fact even the gill- synaptic strength produced by sensitizing stimuli to the withdrawal reflex, perhaps the simplest behavioral reflex tail. In 1976 Brunelli et al., [24] found that serotonin of Aplysia, can be modified by five different forms of increases the level of cAMP in the sensory neurons. learning: habituation, dishabituation, sensitization, clas- cAMP (Cyclic Adenosine Monophosphate) had been sical conditioning, and operant conditioning [15]. discovered in 1958 by Earl Sutherland of Case Western The availability of these simple systems opened up the Reserve as an intracellular “second” messenger that is first analyses of the mechanisms of memory, which fo- activated in response to certain hormones – the “first” cused initially on short-term changes lasting from a few messengers – such as epinephrine, that by themselves minutes to an hour. These studies found that one me- cannot pass through the cell membrane [29]. For this chanism for learning and short-term memory evident in discovery, Sutherland was awarded the Nobel Prize in both the gill-withdrawal reflex of Aplysia and in the tail Physiology or Medicine in 1971 [29]. To test the idea flick response of crayfish is a change in synaptic strength that serotonin produces its effects on sensitization by brought about by modulating the release of transmitter. means of cAMP, Brunelli et al. [24] next injected cAMP A decrease in transmitter release is associated with directly into the sensory neurons and found that this short-term habituation whereas an increase in transmit- resultant increase in the level of cAMP indeed led to a ter release occurs during short-term dishabituation and transient enhancement of transmitter release in the syn- sensitization ([16-20]; for early reviews, see [21,22]). aptic connection between the sensory and motor neuron Studies of memory in invertebrates also delineated a of the gill-withdrawal reflex. family of psychological concepts paralleling those first By the time Brunelli et al. did their first experiment, it described in vertebrates by the classical behaviorists (Pav- was already known that cAMP mediates almost all of its lov and Thorndike) and their modern counterparts actions through a kinase – an enzyme that phosphory- (Kamin, Rescorla, and Wagner). These concepts include lates proteins – called the cAMP-dependent protein the distinction between various forms of associative and kinase or protein kinase A (PKA). PKA had been disco- nonassociative learning and the insight that contingency – vered in 1968, a decade after the discovery of cAMP by that the conditioned stimulus, in associative learning, is Sutherland, by Edwin Krebs and Edmond Fischer, thereby predictive of the unconditional stimulus - is more critical establishing a mechanism not only for cAMP, but also a for learning than mere contiguity: the CS preceding the US class of general mechanisms for second messenger signal- (for review see [23]). Here, for the first time, psychological ing inside of cells [30]. In fact, PKA has served as a proto- concepts, which had been inferred from purely behavioral type for understanding other protein kinases and for studies, could be explained in terms of their underlying cel- appreciating the role of phosphorylation and dephospho- lular and molecular mechanisms. For example, the finding rylation as a rapid and reversible means of modifying the that the same sensory to motor neuron synapses that activity of proteins. Krebs was also able to establish that mediate the gill-withdrawal reflex are the cellular sub- the enzyme PKA is made up of four subunits: two regula- strates of learning and memory illustrates that the storage tory subunits that inhibit two catalytic subunits. The cata- of procedural memory does not depend on specialized, lytic subunits are the active phophorylating portions of superimposed memory neurons whose only function is to the enzyme. When the level of cAMP rises in cells, the store rather than process information. Rather, the capability cAMP binds to the regulatory subunits of PKA, causing for simple procedural memory storage is built into the them to undergo a conformational change that frees the neural architecture of the reflex pathway. active catalytic subunits and allows it to phosphorylate its substrates. For this work, Fischer and Krebs were awarded Emergence of a molecular biology of the Nobel Prize in Physiology or Medicine in 1992. memory-related synaptic plasticity In 1980 Castellucci et al. [17] injected the catalytic sub- The delineation of cAMP and PKA in short-term unit of PKA directly into the sensory neurons, and found memory storage that this was also sufficient to enhance transmitter release Cell biological studies of the synaptic connections between at the synaptic connection between the sensory neuron the sensory and motor neurons of the gill-withdrawal and the motor neuron.