Principal Investigator Martha Constantine-Paton
These studies aim to dissect the events downstream of NMDAR function at young synapses in order to understand how activation of this receptor is linked to dynamic changes in young neuronal contacts. These changes include filopodial motility, neurite elongation, “compensatory” sprouting of a remaining projection when a converging input is removed and the stabilization of inputs that are most effective in activating NMDAR currents. Some of these studies utilize primary Xenopus or rodent visual neurons in tissue culture in conjunction with studies that alter their activity, examine morphological changes over time and meaure Ca++ influx. We are also currently using a GFP transgenic mouse in which, via adenovirus transfection, RFP labeled synaptic vesicles allow visualization of changes in a small population of presynaptic processes adjacent to GFP labeled dendrites whose activity can be controlled by voltage-clamping.
Another set of studies are aimed at identifying the specific molecular changes at synapses that are immediately downstream of NMDAR activity in young neurons. For example, we have found that controlled eye-opening in rat pups trigger a major trafficking of PSD-95 to visual synapses within 6 hours of eye-opening. This biochemical change is associated with the rapid appearance of new NMDAR currents followed by changes in AMPAR currents typical of LTP.
Finally, we have begun to explore the regulation of glutamate receptors in neurological disease. Thus, with collaboration at Massachusetts General Hospital, we have begun to examine glutamate receptors on normal motorneurons and in transgenic mice carrying a mutant superoxide dismutase gene that has been linked to familiar amyotrophic lateral sclerosis (ALS).