CREB: A Mediator of Long-Term Memory from Mollusks to Mammals Minireview (1994)

David A. Frank’tt and Michael E. Greenberg’t *Department of Neurology Division of Neuroscience Children’s Hospital Boston, Massachusetts 02115 tDepartment of Neurobiology Harvard Medical School Boston, Massachusetts 02115 *Dana-Farber Cancer Institute Boston, Massachusetts 02115 Our ability to recall past events in large part determines our uniqueness as individuals. Understanding the molec- ular mechanisms of learning and memory has been a major area of investigation in neurobiology. Recent work suggests that the encoding of long-term memories may involve similar mechanisms from invertebrates to mammals. Several papers in the current issue of Cell give further strength to this hypothesis and demonstrate that a single transcription factor, termed CREB (for CAMP response element-binding protein), is critical to the process. CAMP and Memory The molecular dissection of a phenomenon as complex as memory requires analysis by a number of different ap- proaches. Among those used, three have been particularly fruitful: analyzing a simple response in a simple organism to establish an in vitro model of learning and memory, taking a genetic approach to define and to perturb specific pathways that may be critical for memory formation, and studying the electrophysiologic underpinnings of a brain region that is responsible for encoding new memories. In addition to vastly expanding our understanding of the mechanisms of memory, these three approaches have all suggested that a CAMP-regulated signaling pathway plays a key role in the processes of learning and memory. Aplysia The ability to modulate an action after repetitive stimula- tion is an ancient trait in evolution and represents the most basic form of learning. The invertebrate mollusk Aplysia has been invaluable in studying this phenomenon. A nox- ious stimulus to the tail of this animal leads to the with- drawal of its gill. A single such provocation will, for a brief period of time, lead to an enhanced response to a subse- quent stimulus. This short-term facilitation or memory dif- fers from that induced by multiple stimuli, which leads to an enhanced response for a prolonged period. New protein synthesis is required for the establishment only of the long- term effect (Montarolo et al., 1988). This simple model for learning can be replicated in vitro by coculturing a single Aplysia sensory neuron with a sin- gle Aplysia motor neuron. These two cells form a synapse, and the introduction of serotonin, a neurotransmitter re- leased by interneurons after stimulation of the Aplysia tail, can lead to increased signaling across this synapse (Monta- rolo et al., 1986; Rayport and Schacher, 1986). Serotonin binds to its receptor on the presynaptic sensory neuron, leading to the activation of adenylyl cyclase and to the generation of the second messenger, CAMP. Subsequently, the amount of neurotransmitter released from sensory neuron following each action potential is increased. The effect of serotonin can be mimicked by the direct injection CAMP into the sensory neuron, which can trig- ger both short- and long-term facilitation (Schacher et al., 1988); conversely, inhibitors of CAMP-dependent protein kinase A (PKA) block both forms of facilitation (Ghirardi et al., 1992). The conclusion from this experiment is that CAMP is critical for a simple form of learning in Aplysia. Drosophila The importance of the CAMP signaling pathway for mem- ory formation has also been demonstrated in other organ- isms. The ability to teach flies associate a particular odor with an electric shock led to the identification of several mutants with defects in learning whose molecular nature could be discerned. One, the dunce mutation, results in a deficiency in CAMP phosphodiesterase (Byers et al., 1981). Another, the rutabaga mutant, has a defect in cal- ciumlcalmodulin-responsive adenylyl cyclase (Levin et al., 1992). Thus, the absence of either these two enzymes, one of which breaks down CAMP, the other of which gener- ates it, leads to a profound learning defect. As with simple memory in Aplysia, learning in Drosophila has two phases. A paper in this issue of Cell dissects asso- ciative learning in Drosophila into a short-term component that does not require protein synthesis and a long-term component that does (Tully et al., 1994). In these experi- ments, a relatively short-term memory was produced by conducting training sessions consecutively, without a rest interval. This massed training led to a type of learning called anesthesia-resistant memory (ARM). As indicated by its name, ARM is maintained under conditions of cold shock anesthesia (chilling the flies to 0% for 2 min), and it can be established in the presence of protein synthesis inhibitors. In contrast with ARM, when wild-type flies are subjected to training sessions that are separated by a 15 min rest period (so-called spaced training), long-term memory oc- curs that persists for at least 7 days and is inhibited by presence the protein synthesis inhibitor cyclohexemide. When a new Drosophila mutant termed radish (Folkers et al., 1993) was tested under these conditions, the mutant flies were found to have a defect in ARM but not in long- term memory. These observations strengthened the con- clusion that the short-term and long-term forms of memory are different. The short-term form is not a requisite for the long-term process and the long-term form depends on protein synthesis. Mammals The experiments described in two additional papers in this issue of Cell extend to mammals previous findings that implicate CAMP pathways in the short- and long- term forms of memory. Long-term declarative memories, those concerning facts, ideas, and images, require in part