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Faculty List
Mary B. Kennedy
kennedym@caltech.edu
Ph.D., 1975, John's Hopkins University
Molecular Structure and Function of Central Nervous System Synapses
How does your brain store new information; the face of an acquaintance, the license plate of your new car, or the movements required to throw a baseball? Neurons communicate primarily through chemical synapses that transmit signals by releasing transmitters that cause electrical changes in target neurons. Many of these same transmitters also initiate biochemical changes in the signalling machinery of the synapse itself. Such biochemical "plasticity" is fundamental for information processing and storage in the brain. For example, it is now thought that memories are encoded when the signalling strength of appropriate synapses is permanently increased through biochemical mechanisms triggered by the repeated use of the synapse.
Neurotransmitters can trigger the activation of several signal transduction pathways. We are studying the molecular organization of signal transduction systems in central nervous system synapses. We have found that the postsynaptic density, a specialization of the submembranous cytoskeleton seen at postsynaptic sites in the central nervous system, contains signal transduction molecules that may control the sensitivity of transmitter receptors, the size of receptor clusters, or perhaps the integrity of the adhesion junction that holds presynaptic terminals in place. Employing a combination of microchemical and recombinant DNA techniques, we have determined the structure of several proteins associated with postsynaptic densities. We are presently studying the associations of these proteins with each other and their specific roles in control of synaptic transmission with the ultimate goal of illuminating the function and the biochemical diversity of this specialized organelle.
In a related project, we found that a neuronal calcium/calmodulin-dependent protein kinase (CaM kinase II), which transfers phosphate from ATP to specific proteins, is concentrated in the postsynaptic density and may play an important role in controlling changes in synaptic strength that underlie memory formation in the mammalian hippocampus. This enzyme is activated by autophosphorylation of a threonine located near the calmodulin-binding site. We have developed a new technique to correlate changes in phosphorylation of CaM kinase II and other proteins at synapses in situ with changes in neuronal physiology. This technique involves the use of antibodies that bind only to a particular phosphorylated site on a protein to visualize changes in phosphorylation of the protein in cultured neurons and in brain slices. It provides unprecedented spatial resolution of protein phosphorylation in tissues.
Localization of postsynaptic proteins in a cultured neuron by immunocytochemistry. Antibodies to the NMDA receptor are labeled green. Antibodies to PSD-95 are labeled red. Both proteins are concentrated in the yellow patches along the dendrites.
