Education and Training
1983: Ph.D., University of Washington
Areas of Interest
Components of the cell are positioned and compartmentalized with exquisite precision, but the functional significance of this organization has only recently been recognized. Spatial complexity is especially prominent within the nervous system. My research addresses the organization of excitatory synapses in rodent neocortex and hippocampus. Techniques routinely used in my lab include high-resolution and quantitative light- and electron microscopic immunocytochemistry.
We performed a number of studies using light microscopic immunocytochemistry and immunogold EM to examine the relationship of AMPA and NMDA glutamate receptors to the synaptic active zone. We continue this basic line of research: Proteomics studies have identified over 100 proteins associated with the postsynaptic density (PSD). We are using quantitative immunogold methods and high-resolution electron tomography to examine the organization of a variety of these proteins, to elucidate the supramolecular architecture of the PSD. We want to use this information to explore how the organization of molecules within the synapse may help to regulate postsynaptic signaling pathways. For example, calcium ions entering through NMDA receptor channels may modify synaptic activity. Might the targets of this calcium entry (e.g., CaMKII, nNOS, or calcium-dependent adenylyl cyclase) be situated close to the NMDA pore, suitably positioned to respond selectively to calcium entry through that pore? Likewise, might specific enzymes (e.g., PKA) that can modulate AMPA receptors be held close to these receptors?
This leads to a second theme in my research, to study the anatomical basis of synaptic plasticity. Of particular interest to us is the nitric oxide/sGC signaling pathway (implicated in modulation of presynaptic release) and trafficking of AMPA receptors (implicated in the control of postsynaptic efficacy). The issue of trafficking has led us to study motor and endocytic proteins, in relation to the actin cytoskeleton.
A final theme of my current research is to explore calcium sinks and sources within dendritic spines. My lab is part of a multi-center program project grant (with Mary Kennedy, Karel Svoboda, and Terry Sejnowski), using a multidisciplinary approach to elucidate the functional significance of spines. So far, my group has focused on the organization of plasma membrane calcium pumps (PMCAs), which appear to play a considerably more complex role in calcium signaling than was previously recognized.