The study was published in the September 9, 2010 edition (Vol. 67, No. 5) of the journal Neuron.
"This is the first time we have a new memory and learning gene that lies outside what has been considered the most fundamental signaling pathway that underlies learning in the fruit fly," said Ron Davis, chair of Scripps Research Department of Neuroscience who led the study. "Since many of the learning and memory genes originally identified in the fruit fly are clearly involved in human neurological or psychiatric diseases, this discovery may offer significant new insights into multiple neurological disorders. We're definitely in the right ballpark."
The study shows that different alleles or mutant forms of the gene, known as gilgamesh (gish), are required for short-term memory formation in Drosophila olfactory associative learning – learning that links a specific odor with a negative or positive reinforcer.
Because Drosophila learning genes are known to be conserved in higher organisms including humans, they often provide new insights into human brain disorders. For example, the Drosophila gene known as dunce, which Davis helped identify several years ago, provided clues to the genetics of the devastating psychiatric condition of schizophrenia. Recent studies have revealed that the human version of the dunce gene is a susceptibility determinant for schizophrenia. In a similar way, any new learning gene identified in Drosophila, including gilgamesh, may provide new clues to genes involved in human neurological or psychiatric disorders.
"We're still early in the process of making connections between Drosophila memory and learning genes and the pathology of human disease," Davis said, "but it's already clear that many of these genes will provide important conceptual information and potential insights into human brain disorders. In addition, there is every reason to believe that their gene products will be one day become the target of new drugs to enhance cognition. Uncovering this new gene and its signaling pathway helps bring us that much closer to this goal."
New Gene, New Pathway
To identify the new gene, Davis and his colleagues used a novel screen for new memory mutants, looking for lines that showed abnormal learning when only one of two copies of the gene was mutant.
"We used a dominant screen because we realized that behavior such as learning and memory are very sensitive to gene dosage," Davis said. "That is, the mutation of just one copy of a gene involved in behavior is often sufficient to produce an abnormality."
The formation of new memories occurs, in part, through the activation of molecular signaling pathways within neurons that comprise the neural circuitry for learning, and for storing and retrieving those memories.
One of the things that makes the function of gish so interesting, Davis noted, is the fact that it is independent of mutations of the rutabaga gene, a Drosophila memory-learning pathway that is known to be essential for memory formation. The rutabaga mutants convert ATP, the energy chip of cells, into cyclic AMP or cAMP, which plays a critical role in olfactory learning in Drosophila.
"The cAMP pathway is the major signaling pathway used by Drosophila neurons to turn on other enzymes and genes that are necessary for memories to form," Davis said. "In fruit flies, memory and learning revolves around mutants of this pathway. It is fundamental to the process."
In the new study, gish provided an answer to a longstanding problem in Drosophila learning and memory research – the unexplained residual memory performance of flies carrying rutabaga mutations, which indicated the existence of an independent signaling pathway for memory formation. While other memory mutants have been identified, until the discovery of gish none have been shown to reduce the residual learning of mutant rutabaga flies.
Interestingly, the study found that the gish gene encodes a kind of casein kinase (which help regulate signal pathways in cells) called Iγ (CKIγ). This is the first time that this specific kinase has been cited as having a role in memory formation.
The identification of all signaling pathways that are engaged in specific neurons during memory formation and how they interact with one another to encode memories is an issue of great importance, Davis said, one that needs more exploration for a deeper understanding of memory formation and memory failure in humans.
"The truth is that we have an extremely sketchy understanding of what causes diseases like Alzheimer's," Davis said. "We need to understand a lot more than we do now about normal brain functions like memory and learning before we have a high probability of succeeding in the development of a cure."
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The first author of the study, "Gilgamesh is required for Rutabaga-independent Olfactory Learning in Drosophila," is Ying Tan of Baylor College of Medicine. Other authors include Dinghui Yu and Jennifer Pletting of Baylor College of Medicine.
The study was supported by the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, Scripps Research currently employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida. For more information, see www.scripps.edu
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