PII S0361-9230(99)00124-0 cAMP and memory: A seminal lesson from Drosophila and Aplysia Alcino J. Silva* and Geoffrey G. Murphy Departments of Neurobiology, Psychiatry, Psychology, and Brain Research Institute, University of California, Los Angeles, CA, USA [Received 10 May 1999; Accepted 10 May 1999] BACKGROUND Uncovering the molecular and cellular nature of learning and memory is perhaps one of the most far reaching, yet, realistic, goals for neuroscience in the next century. This quest originates more than 30 years ago in studies of two invertebrate model systems that continue to play a central role in molecular neuro- science: Aplysia and Drosophila. The startling facet of this story is that independently—and despite using fundamentally different ap- proaches and techniques—the studies of Aplysia and Drosophila both revealed that activation of the cyclic adenosine monophos- phate (cAMP) signaling pathway played a critical role in learning and memory processes. Because molecular neurobiology currently permeates almost every aspect of neuroscience research, it is difficult for many to imagine a time when molecular mechanisms were thought to have no direct role in cognitive processes such as learning and memory. However, even within the last 5 years, there have been several opinion papers published in top neuroscience journals deriding molecular studies of behavior, dismissing them as naı ¨ve misguided reductionism. Similarly, the very idea that specific molecular events underlie different aspects and phases of memory, and there- fore that the manipulation of single genes and proteins could affect memory in specific and revealing ways, has been the subject of great debate until only recently. In the not too distant past, learning and memory was viewed as the exclusive property of complex and mysterious circuit events. In contrast, molecules were though to have a general role in memory, analogous to the role of silicon in computer chips: required because of their physical properties, but possessing no specific computational function. However, the sem- inal experiments outlined below changed this viewpoint forever and opened the door for much of the learning and memory research that is being conducted today. HIGHLIGHT In an elegant series of studies that began in the early 1970s, Eric Kandel and his colleagues at Colombia University captured in a reduced cellular preparation the essential properties of a simple form of non-associative form of learning in Aplysia known as sensitization (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 not possible in most other systems (see also studies in Hermissenda [1]). Mild tactile stimulation of the siphon of this marine mollusc triggers a defensive withdrawal reflex that includes the retrac- tion of the gill and siphon for a few seconds. However, after a single sensitizing stimulus (e.g., head/tail shock), the same mild tactile stimulation produces a siphon and gill withdrawal reflex that lasts significantly longer. Pharmacological and electrophys- iological studies have shown that the sensitizing stimulus acti- vates a group of modulatory interneurons (some of which are serotonergic) that in turn activate G-protein coupled receptors on the siphon sensory neurons mediating the withdrawal re- sponse. Activation of these receptors stimulates adenylate cy- clase, an enzyme that synthesizes cAMP. The resulting increase in cAMP activates another enzyme (cAMP-dependent protein kinase) which phosphorylates a number of substrates that me- diate both short- and long-term sensitization. Amazingly, an unbiased screen for Pavlovian conditioning mutants in Dro- sophila, initiated in the laboratory of Seymour Benzer at the California Institute of Technology in the mid-1970s, also re- vealed evidence for the involvement of cAMP signaling in learning and memory. In fact, three out of the four learning and memory mutations found to date in genetic screens Drosophila code for members of the cAMP-signaling pathway. For exam- ple, the first mutant to be discovered by Benzer and colleagues named dunce [4], lacks a phosphodiesterase that degrades cAMP [3]. Importantly, these findings have recently been ex- tended into vertebrates, where electrophysiological and behav- ioral studies have confirmed the critical importance of cAMP signaling to learning and memory (for recent review see [6]). SIGNIFICANCE The elegant experiments in Aplysia and Drosophila mentioned above demonstrated that molecular explanations of memory could not be summarily dismissed. It is important to note that these pioneering studies, and the work that has followed in Aplysia and Drosophila (as well as a number of other model organisms) do not demonstrate that memory can be explained solely by molecular * Address for correspondence: Prof. Alcino J. Silva, University of California, Los Angeles, Depts. of Neurobiology, Psychiatry, Psychology, and Brain Research Institute, 695 Young Drive South, Room 2554, Box 951761, Los Angeles, CA 90095-1761, USA. E-mail: silvaa@ucla.edu Brain Research Bulletin, Vol. 50, Nos. 5/6, pp. 441– 442, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0361-9230/99/$–see front matter 441