(Taken from the Candidate's Abstract) The widespread use of lead has made lead exposure a serious environmental and occupational hazard. Children are particularly vulnerable to the effects of lead and exposure can cause serious cognitive and behavioral deficits. Although lead is a known environmental neurotoxin, the physiological bases of this toxicity remain unclear. However, evidence suggests that the NMDA-type glutamate receptor function is down-regulated by lead, and this down regulation attenuates long-term potentiation (LTP), a cellular correlate of learning. Recent studies of downregulation have used binding assays and immunocytochemistry to show that binding of agonist is reduced after lead treatment. While these studies provide valuable information, they are not functional assays of receptors in intact tissue. The candidate will determine how lead modifies NMDA receptor function with a novel, high resolution method of localizing and characterizing receptor function. This method uses local photolysis of caged agonists to isolate 3 um membrane sections in living cells within brain slices. The candidate will combine whole-cell voltage clamp recordings, local photolysis, and calcium imaging to examine the effect of NMDA receptor downregulation on long-term potentiation and long-term depression. She hypothesizes that lead decreases NMDA receptor function by decreasing expression of functional receptors, changing receptor subunit composition, and altering calcium permeability, which attenuates LTP and LTD. These experiments will provide a basis for examination of the downstream processes initiated by receptor activation.
|Harris, Alexander Z; Pettit, Diana L (2008) Recruiting extrasynaptic NMDA receptors augments synaptic signaling. J Neurophysiol 99:524-33|
|Harris, Alexander Z; Pettit, Diana L (2007) Extrasynaptic and synaptic NMDA receptors form stable and uniform pools in rat hippocampal slices. J Physiol 584:509-19|