Mechanisms of synaptic structure and function during development

The synapse is the fundamental unit of function in the nervous system. Understanding how synapses form, how they grow throughout development, and how their structure and function are molded by neuronal activity are central questions in neurobiology. A satisfying explanation for how we learn, remember, and think--and insights into how neurological and psychiatric diseases disrupt these processes--will require a deep understanding of synaptic development, function, and plasticity. To investigate the molecular mechanisms that regulate the functional and morphological development of synapses we combine genetic, neuroanatomical, and electrophysiological studies in both Drosophila and the mouse. To investigate processes that regulate synaptic strength we focus on two questions--1) What mechanisms and molecules regulate the localization of glutamate receptors to the postsynaptic density? and 2) What factors control the filling of synaptic vesicles with glutamate, and do presynaptic changes in vesicle content regulate the strength of synapses?

In our studies of the morphological development of synapses we focus on a key negative regulator of synaptic growth, a protein called highwire in Drosophila. In the absence of highwire there is dramatic overgrowth of synapses and those synapses have impaired synaptic release. Highwire functions as a ubiquitin ligase and we are currently using biochemical and genetic techniques to characterize the synaptogenic signal pathways regulated by highwire. In addition, we have identified a single homolog of highwire in the mouse, termed Phr, that is highly expressed in the developing brain. We have generated constitutive and conditional knock outs of Phr and we are characterizing the function of Phr for the development, maintenance, stability, and function of mammalian synapses.