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Thirty years ago, a few of us in Seymour Benzer's laboratory set out to identify the machinery underlying learning and memory in fruit flies by isolating mutant strains that learned poorly, and by mapping and finding the genes. This effort paid off quickly with the mutants, dunce and rutabaga, which affect enzymes in the cyclic AMP (cAMP) cascade. Acutely perturbing the activity of camp-dependent protein kinase disrupts a fly's ability to learn, ruling out indirect effects on development. Disrupting the activity of the camp-activated transcription factor CREB also disrupts the fly's long-term memory. These pathways are essential for learning in invertebrates and mammals. As breeding populations and testing all of them in learning paradigms, is brutally labor-intensive, compensatory mutations (dunce mutant flies lack a cyclic AMP metabolizing enzyme whereas amnesiac flies have an almost opposite defect in a camp-stimulatory neuropeptide) provide a shortcut whereby two mutations complement each other to restore female fertility. The lab has started a generalized screen for secondary mutations that suppress dunce's female sterility, and they have isolated several intriguing new genes including novel transcription factors and second-messenger molecules.

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