My principal scientific interest has been the role of genes in directing neural development and behavior. I began this work as a graduate student with Jeffrey Hall at Brandeis University, studying neurotransmitter mutations in the fruit fly Drosophila melanogaster, receiving my Ph.D. in 1979. I went on to UCSF, Princeton University, and the Roche Institute of Molecular Biology to study mutants affecting early neural development in mouse and fly embryos. In recent years, I have returned to the study of behavior in the fruit fly. The genetic mechanisms underlying behavior and development are not as different as they may seem, since developmental processes put together the circuitry and machinery underlying behavior.

My research makes use of genetic and molecular manipulations in the fruit fly to study the interplay between plasticity and programming in the nervous system. This approach offers a powerful strategy for defining the genes involved in developmental cell interactions and in the signalling mechanisms utilized in behavioral and physiological plasticity.

The calcium/calmodulin-dependent protein kinase (CaM kinase II) has been implicated as a mediator of plasticity in the nervous system. To study its role in neural plasticity, we have developed techniques to manipulate its activity in vivo, by expressing a synthetic gene for a specific inhibitory peptide in neurons. Flies carrying this gene are abnormal in synaptic plasticity during development and in experience-dependent behavior as adults. In addition, they display physiogical alterations after short-term repetitive stimulation, appearing as an inability for presynaptic cells to repolarize properly. We are now trying to identify other steps in the pathways served by CaM kinase II and also to identify the dorsal brain circuits that are being affected in their plasticity.

We have gone on to identify one candidate target for the kinase based on phenotypic similarity between mutants. Mutants in the eag gene, encoding a putative potassium channel subunit, display an alteration in synaptic transmission at the neuromuscular junction very similar to that in flies inhibited for CaM kinase II. Following these observations, we have demonstrated in vitro phosphorylation of the eag protein by purified CaM kinase II, suggesting that neurons may use CaM kinase II phosphorylation of eag to compensate for the effects of repetitive stimulation by reducing outward potassium currents, as part of short-term plasticity. We have also recently developed an analogous system for studying protein kinase C (PKC).