This study will focus on the effect of neurotransmitters on ion channels in the hippocampus, and their possible relevance for senile dementia of the Alzheimer's type (SDAT). Phase I will focus on the action of various neurotransmitters in rat hippocampus, with particular emphasis on their effect on specific ion channels. Whole cell and single channel patch clamp analysis of dissociated rat hippocampal cells will be employed to study the response of specific ion channels to acetylcholine and norepinephrine. Parallel studies on the effect of various presumed second messengers should shed light on the mechanism of action of these neurotransmitters in the central nervous system. Since a deficiency of these two neurotransmitter systems in the hippocampus has been implicated in SDAT, this may allow for a better physiologic understanding of how their pathologic involvement leads to the clinical manifestations of the disease. In addition, ion channels are a potential site of pharmacologic manipulation. 4-aminopyridine, a potassium channel blocker, has been shown in a preliminary trial to improve memory in SDAT. Patch clamp analysis of the effect of 4-aminopyridine and related compounds on the various potassium channels of the hippocampal cell will be studied. In phase II, an attempt will be made to develop model systems for the study of ion channels from human tissue. The potential demonstration of similarities in physiologic response of specific ion channels from rat lymphocytes and rat hippocampal cells should allow for extrapolation from human lymphocytes to human hippocampus. Therefore, the first approach will initially involve the patch clamp analysis of rat lymphocytes which have been shown to have a muscarinic receptor, as well as to have a physiologic response to acetylcholine. This will be followed by similar analysis of human lymphocytes. The second approach will involve expression of ion channels from human brain tissue obtained at autopsy in either frog oocytes, or in tissue culture cells. This should allow for the physiologic study of human ion channels in these systems. These two approaches will permit comparative study of the ion channels from various human populations, including patients with SDAT, their affected and nonaffected relatives, and young and aged controls. Finally, these two systems can serve as model systems for the testing of drugs on human ion channels.
