Ph.D., University of Massachusetts Medical School, 1990
B.A., Assumption College, 1984
University of Wisconsin, 1992-1995
Genetic Analysis of Neural Function
Our research is focused on genetic analysis of neural function in health and disease. This work is carried out primarily in the Drosophila genetic model system along with selected studies in mouse. Two major objectives in our current research are to examine the molecular basis of chemical synaptic transmission and neurodegeneration.
Chemical synaptic transmission is the primary mechanism by which electrical signals are transmitted among nerve cells (neurons). At the synapse, chemical neurotransmitter is released from the presynaptic (transmitting) neuron and acts through receptors on the postsynaptic (receiving) cell membrane. One interesting aspect of this process is the highly regulated and rapid form of exocytosis that is responsible for neurotransmitter release. Although the molecular mechanisms of neurotransmitter release remain incompletely understood, intensive work in the field has implicated numerous proteins. Ideally, the functions of these and additional proteins in the release process can be defined by specific perturbation of individual gene products, followed by in vivo functional analysis at native synapses. Our laboratory utilizes the fruit fly, Drosophila melanogaster, as a model experimental system in which synaptic mechanisms similar to those of vertebrates may be studied in vivo, using a powerful combination of genetic, molecular, biochemical, electrophysiological, and imaging approaches. Genetic screens identify mutants defective in synaptic transmission; molecular and biochemical studies identify, characterize, and manipulate the affected proteins; and electrophysiology, fluorescence microscopy and ultrastructural methods are used to investigate the in vivo function of the protein at native synapses. Ongoing studies involve analysis of temperature-sensitive (TS) mutants which exhibit rapid paralysis and failure of synaptic transmission when exposed to elevated temperatures. Such conditional mutants allow normal organismal development and function at permissive temperature, while permitting acute perturbation of a specific gene product in the mature animal. These features make TS paralytic mutants a unique and powerful tool for analyzing the in vivo physiological functions of specific proteins in synaptic transmission.
In addition to mechanisms of neurotransmitter release, our work has examined the role of perisynaptic glial cells in synaptic transmission. Many synapses include not only presynaptic and postsynaptic elements, but also a glial cell process which contributes a third structural and functional component. These tripartite synapses play critical roles in the nervous system and much remains to be learned about the functional contributions of glia. Our genetic analysis of synaptic transmission has extended to a tripartite synapse model in Drosophila and the properties of participating perisynaptic glial cells.
Neurodegeneration, or neuronal cell death, leads to prevalent and devastating neurological diseases such as Alzheimer's and Parkinson's. Our studies have developed a new experimental model for genetic analysis of neurodegenerative mechanisms in Drosophila and include genetic screens for new mutations which suppress neurodegeneration. Such unbiased phenotypic screening in the organism facilitates identification and in vivoanalysis of gene products functioning in this process. Ongoing studies of new mutants which are resistant to neurodegeneration may provide new insights into both the molecular basis of neurodegenerative mechanisms and the development of rational therapies to control them.