The goal of my research is to understand the cell biological mechanisms underlying plasticity and stability of neurons. The mammalian brain undergoes dramatic developmental changes after birth to attain neural functions that reflect the experience of early life. Once mature, the pathways of the brain become more stable while maintaining a certain degree of plasticity. I am investigating how catecholamines and acetylcholine in the neocortex regulate plasticity via interactions with amino acid neurotransmitters during postnatal development and in adulthood.
My research while a graduate fellow in the laboratory of Dr. Philip Siekevitz at the Rockefeller University showed that there is a functional link between neuronal activity, second messengers, and phosphorylation of a cytoskeletal protein--MAP2--during the critical period for visual cortex development. These results suggest that neuronal plasticity may depend on the malleability of cell shape, which, in turn, is dependent on the state of phosphorylation of cytoskeletal proteins. For this work, I received a Ph.D. degree in 1985.
For my postdoctoral training, I joined the laboratory of Dr. Virginia M. Pickel at the Department of Neurology and Neuroscience, The Cornell University Weill Medical College, where I learned how to visualize two types of molecules simultaneously at a level of resolution afforded by an electron microscope, so that molecular interactions at newly forming and well- established synapses could be probed. Using this technique, I have shown that (1) catecholamines diffuse beyond the synaptic cleft to activate receptors at sites that lack ultrastructural features of synapses; (2) glia extend fine processes around glutamatergic synapses to aid in converting neuronally released glutamate to its non-toxic form, glutamine; (3) the novel neuronal messenger--nitric oxide--can be generated both pre- and postsynaptically and within spines expressing NMDA receptors; and (4) NMDA receptors occur both pre- and postsynaptically; (5) NMDA receptor clusters can be found at nonsynaptic sites of dendritic shafts and somata during early life, prior to the arrival of afferents.
My current research continues to use electron microscopic techniques to examine the cellular bases of interaction between transmitters and receptors that are thought to have important roles in synaptic plasticity. By using the electron microscope, we have observed that neurotransmitter receptors are brought to the pre- and postsynaptic membrane in an activity-dependent manner. This response is measurable within tens of minutes within adult cortices. We have a hunch that cytoskeletal proteins are involved in the activity-dependent trafficking of synaptic molecules within dendritic spines and axon terminals. Thus, we are exploring the impact of the appearance or removal of two candidate molecules that link the recruitment of synaptic molecules to newly forming synapses: drebrin, for the postsynaptic membrane and neurexin, for the axon terminals.
Another interest of mine is to understand the cellular and molecular mechanisms underlying cholinergic and GABAergic modulation. Why are there so many different types of cholinergic and GABAergic receptors in the brain? I am particularly interested in the way that GABAergic receptors contribute to the regulation of anxiety through modulation of hippocampal and amygdala neurons. We are exploring the possibility that the various types of receptors may be distributed in a pathway-specific manner within single brain regions, thereby allowing for multifaceted mode of modulation of excitatory and inhibitory synapses. Our method of approach is to combine electrophysiological measurements of neuronal responses to the application of receptor-specific agonists and antagonists and then to relate this activity pattern to the ultrastructural distribution of receptor proteins at pathway-specific synapses.