A number of calcium (Ca2+)-dependent systems have been reported to decline with aging. Impaired Ca2+ homeostasis has recently emerged as a well documented manifestation of aging and, in addition, may contribute to several neurodegenerative disorders such as senile dementia. The precise cellular mechanisms involved in this change in Ca2+ homeostasis have not been determined. The purpose of this proposal will be to characterize changes in Ca2+ ion regulation in identified neurons of the basal forebrain during maturation and aging. These neurons were chosen because they play a pivotal role in memory and cognition as well as having relevance to the clinical symptoms of several neurological disorders. We will test the hypothesis that there is an age-related and cell-specific decline in voltage-gated Ca2+ channel (VGCC) function during aging. This hypothesis will be tested by investigating three key aspects of Ca2+ regulation including; a) Ca2+ entry through VGCC using both whole-cell and single- channel patch-clamp recordings, b) free cytosolic Ca2+ concentrations using microfluorometric techniques, and c) regulation of VGCC by neurotransmitter systems known to control voltage-dependent Ca2+ movement. All of these parameters could regulate VGCCs through direct actions on ion gating, alterations in free cytosolic Ca2+, or indirect changes involving signal transduction and second messenger modulation. Experiments will be performed using Fischer 344 rats (1 month, 12 month and 20 month age groups) in two in vitro preparations; either acutely dissociated cells or in a thin brain slice preparation. The thin slice preparation will also enable us to identify cholinergic versus noncholinergic neurons using double-labelling techniques. Many age-related deficits have been shown to be partially, if not completely, reversed by restoration of appropriate cellular Ca2+ levels or fluxes, suggesting control over neuronal Ca2+ regulation has legitimate therapeutic potential. Results from these experiments will not only provide new quantitative information concerning age-related control of neuronal Ca2+ homeostasis but, more importantly, provide direction for future therapeutic treatments.