cAMP and memory: a seminal lesson from Drosophila and Aplysia.

BACKGROUNDUncovering the molecular and cellular nature of learning andmemory is perhaps one of the most far reaching, yet, realistic,goals for neuroscience in the next century. This quest originatesmore than 30 years ago in studies of two invertebrate modelsystems that continue to play a central role in molecular neuro-science: Aplysia and Drosophila. The startling facet of this story isthat independently—and despite using fundamentally different ap-proaches and techniques—the studies of Aplysia and Drosophilaboth revealed that activation of the cyclic adenosine monophos-phate (cAMP) signaling pathway played a critical role in learningand memory processes.Because molecular neurobiology currently permeates almostevery aspect of neuroscience research, it is difﬁcult for many toimagine a time when molecular mechanisms were thought to haveno direct role in cognitive processes such as learning and memory.However, even within the last 5 years, there have been severalopinion papers published in top neuroscience journals deridingmolecular studies of behavior, dismissing them as nai¨ve misguidedreductionism. Similarly, the very idea that speciﬁc molecularevents underlie different aspects and phases of memory, and there-fore that the manipulation of single genes and proteins could affectmemory in speciﬁc and revealing ways, has been the subject ofgreat debate until only recently. In the not too distant past, learningand memory was viewed as the exclusive property of complex andmysterious circuit events. In contrast, molecules were though tohave a general role in memory, analogous to the role of silicon incomputer chips: required because of their physical properties, butpossessing no speciﬁc computational function. However, the sem-inal experiments outlined below changed this viewpoint foreverand opened the door for much of the learning and memory researchthat is being conducted today.HIGHLIGHTIn an elegant series of studies that began in the early 1970s,Eric Kandel and his colleagues at Colombia University captured ina reduced cellular preparation the essential properties of a simpleform of non-associative form of learning in Aplysia known assensitization (see [5]; for a more contemporary review see [2]).One key aspect of this preparation is that it is amenable to phar-macological and electrophysiological studies that were simply notpossible in most other systems (see also studies in Hermissenda[1]).Mild tactile stimulation of the siphon of this marine mollusctriggers a defensive withdrawal reﬂex that includes the retrac-tion of the gill and siphon for a few seconds. However, after asingle sensitizing stimulus (e.g., head/tail shock), the same mildtactile stimulation produces a siphon and gill withdrawal reﬂexthat lasts signiﬁcantly longer. Pharmacological and electrophys-iological studies have shown that the sensitizing stimulus acti-vates a group of modulatory interneurons (some of which areserotonergic) that in turn activate G-protein coupled receptorson the siphon sensory neurons mediating the withdrawal re-sponse. Activation of these receptors stimulates adenylate cy-clase, an enzyme that synthesizes cAMP. The resulting increasein cAMP activates another enzyme (cAMP-dependent proteinkinase) which phosphorylates a number of substrates that me-diate both short- and long-term sensitization. Amazingly, anunbiased screen for Pavlovian conditioning mutants in Dro-sophila, initiated in the laboratory of Seymour Benzer at theCalifornia Institute of Technology in the mid-1970s, also re-vealed evidence for the involvement of cAMP signaling inlearning and memory. In fact, three out of the four learning andmemory mutations found to date in genetic screensDrosophilacode for members of the cAMP-signaling pathway. For exam-ple, the ﬁrst mutant to be discovered by Benzer and colleaguesnamed dunce [4], lacks a phosphodiesterase that degradescAMP [3]. Importantly, these ﬁndings have recently been ex-tended into vertebrates, where electrophysiological and behav-ioral studies have conﬁrmed the critical importance of cAMPsignaling to learning and memory (for recent review see [6]).SIGNIFICANCEThe elegant experiments in Aplysia and Drosophila mentionedabove demonstrated that molecular explanations of memory couldnot be summarily dismissed. It is important to note that thesepioneering studies, and the work that has followed in Aplysia andDrosophila (as well as a number of other model organisms) do notdemonstrate that memory can be explained solely by molecular