We use cellular, molecular, biochemical, imaging and electrophysiological approaches to elucidate the molecular mechanisms of plasticity and neurodegeneration. We have developed primary culture models of activity-dependent gene transcription and of HD. These models faithfully recapitulate critical features of these processes and allow us to test hypotheses about their underlying mechanisms. Selected findings are evaluated further in genetically modified mice.

We have contributed to the understanding of mechanisms of plasticity and neurodegeneration in several ways. We found that proteins bound to the cytoplasmic portion of one subtype of glutamate receptor, the N-methyl-D-aspartate receptor, play a critical role coupling local Ca²⁺ influx through the channel to elicit adaptive gene transcription in neurons. This may be a general mechanism by which diverse Ca²⁺ channels achieve specific and distinct neuronal responses. We developed a neuronal model that faithfully recapitulates key features of HD. We showed that the nucleus is a critical subcellular site in which mutant huntingtin (the affected protein in HD) induces neurodegeneration. However, mutant huntingtin need not aggregate into inclusions to induce neurodegeneration. Recently, we developed a new automated imaging system that we call a robotic microscope. The instrument enables us to track living neurons over long time periods and to, quantify quickly the adaptive or maladaptive responses of thousands of neurons. Along with special statistical methods, we now have the ability to determine whether and to what extent a variable that is observed on one day can predict the fate of that neuron on another day. This ability will enable us to unravel confounding cause-and-effect mechanisms.