Department of Anatomy and Cell Biology
M.D., 1984 University of La Plata
Psychiatrist, 1990 University of Buenos Aires
Ph.D., 1993 University of Buenos Aires
Postdoctoral training: Department of Physiology and Neurobiology, The University of Connecticut
Postdoctoral training: Department of Genetics and Neuroscience, Case Western Reserve University School of Medicine
The synapse is the site of functional contact between excitable cells, and is comprised of the pre and postsynaptic terminals, and the molecular machinery required for synaptic transmission. The complexity of the synapse is highlighted by the enormous diversity of proteins and molecular mechanism required for the assembly of a synaptic contact and for the regulation of neurotransmission. The importance of understanding the biological rules that govern the formation of a synaptic contact is underscored by the fact that synapses are the centerpiece of neuronal communication and they become affected in a variety of neurological and mental disorders, including autism, mental retardation, schizophrenia, and Alzheimer’s disease.
The long-term goal of my research is to elucidate the cellular and molecular mechanisms that participate in the assembly of the nervous system. Our studies focus primarily on the role of cell-cell interactions mediated by surface receptors in the formation of a synaptic contact. The main questions that we are trying to address are: 1) Which surface molecules are key players in the development of the synapse, 2) How these proteins transduce signals into the cell, and 3) How these signaling mechanisms influence synaptic physiology.
To address these questions we focus on two main approaches. One is the study of the role of N-cadherin in the structural and functional organization of a synaptic contact. N-cadherin is a cell adhesion receptor abundantly localized at synapses where it contributes to the assembly of the synaptic complex by providing adhesion between synaptic membranes and organizing the underlying actin cytoskeleton. We are currently using the zebrafish as model organism due to its rapid growth, transparency, and the feasibility to introduce a variety of genetic and pharmacological manipulations. Deletion of N-cadherin expression in the whole animal severely alters the growth of motor axons into the myotomes. To understand the role of N-cadherin in this system we induce mosaic expression of wild type proteins or proteins lacking certain domains by using motor neuronal or muscle specific promoters in combination with the UAS-GAL4 expression system. The co-expression of mutated proteins with a fluorescent protein allows us the visualization of the growing axon in the intact embryo. This approach is very useful for manipulating the expression of specific proteins in single cells in an otherwise wild type embryo. By altering the expression of proteins in the motor neuron or in the innervated muscle cells we expect to elucidate the molecular mechanisms by which N-cadherin controls axonal growth and synapse formation.
In addition to the studies on N-cadherin, we are currently investigating novel molecules which are required for the assembly of the synaptic contacts. To identify these molecules, we carried out a genome-wide search for transcripts which become highly expressed at the time synapse formation is being induced. By analyzing the expression profile of these transcripts during neuronal development, and the characteristics of the proteins that they encode, we have identified distinct groups of proteins that become expressed on the neuronal surface precisely at the time synapses are forming. To determine the role of these proteins in synapse development, we use in vitro cell assays of synapse formation. Thereafter, the role of these proteins in the assembly of synaptic contacts is studied in vivo by expressing wild type or mutated protein in the zebrafish or chick embryo using cDNA injections and in-ovo electroporation. With these studies, we expect to identify molecules and mechanisms underlying this important developmental process.