application) Since starting at U.C. Irvine in late 1991, the applicant has established a laboratory studying cellular mechanisms of selective neurodegeneration of relevance to the aging brain. He has obtained independent funding (R01 and private grants), and achieved promotion to the rank of Associate professor, with tenure, in August, 1996. To address the sophisticated mechanistic questions which he intends will constitute the core of his research, it will be necessary to supplement toxicity and histology paradigms with techniques of fluorescent imaging and patch clamp electrophysiology, both powerful tools for studying behaviors of living neurons with which he presently has limited experience. Unfortunately, while experts on campus can provide technical assistance, his present heavy teaching, clinical and administrative duties leave insufficient time for mastery of these techniques. The salary support provided by an ISA, by assuring 80% protected time for research, would immeasurably aid the applicant s career development. The physiologic basis for the highly selective pattern of neurodegeneration seen in many diseases of the aging brain is largely unknown. Recent studies have revealed a potentially important clue: While most AMPA/kainate receptor-gated channels are Ca2+ impermeable, certain populations of neurons, including many types that preferentially degenerate in Alzheimer's disease or ischemia, express AMPA/kainate receptor gating channels with high direct Ca2+ permeability. The present proposal follows from our preliminary studies indicating that the endogenous synaptically released cation, Zn2+ appears to permeate Ca2+-permeable AMPA channels with particular rapidity selectively damaging neurons expressing these channels. Initial experiments will thus seek to examine the cellular and subcellular distribution of Zn2+ and Ca2+ permeable AMPA/kainate channel on hippocampal neurons. Histologic approaches and fluorescent imaging will be employed to localize these channels, and whole-cell patch-clamp techniques will be used to examine their permeabilities to Zn2+ and Ca2+. Subsequent experiments will examine consequences of Zn2+ permeation through these channels. Both neurotoxic and physiologic effects will be assessed, using histological, fluorescence imaging and electrophysiological techniques. It is hoped that these experiments will provide initial clues to physiological effects of Zn2+ that may be of importance to selective neurodegeneration in disease as well as to normal neuronal functioning.
