Very little is known about cellular patterns of brain aging in female mammals or about how brain aging in male or female rodents depends on hormonal status. An increase in L-type voltage-gated Ca2+ channels (LIGCCs)/currents and expression of the L-VGCC alpha1 subunit in hippocampal CA1 neurons and altered recover of [Ca2+]i responses have been found to be among the most consistent cellular/molecular biomarkers of brain aging in male rats and female rabbits. These age changes in Ca2+ homeostasis also appear to contribute directly to impaired plasticity and learning. Estradiol (E2) has been found to be neuroprotective and to counteract a number of aging-related alterations in long-term potentiation/depression (LTP/LTD) and cognitive function, and may retard Alzheimer's disease (AD). However, the molecular/cellular mechanisms that mediate these actions are not understood. Recently, we found a potential link between this cellular aging biomarker (L-VGCCs) and E2 actions, in that E2 downregulated L-VGCCs in hippocampal """"""""zipper"""""""" slices ,f ovariectomized (OVX), aged female rats and in hippocampal cultures. E2 decreases in an ageiependent manner and it has been suggested that this contributes to brain aging and declining function in Females and possibly males. This application proposes to test the hypothesis that declining E2 levels with age are a stimulus for altered Ca2+ homeostasis and increased L-VGCCs in hippocampal neurons, whereas chronic E2 retards development of these cellular and behavioral biomarkers of brain aging. In addition, we will identify cellular/genomic pathways through which E2 regulates L-VGCCs and other aging markers. To carr out these studies we will combine two highly advantageous preparations, the hippocampal """"""""zipper"""""""" slice, and an age-dependent hippocampal cell culture model, with single channel electrophysiology, Ca2 imaging in single cells, and gene expression analyses by real-time PCR and Affymetrix gene chip microarray technology. Recently, we adapted the hippocampal """"""""zipper"""""""" slice for single cell gene expression/function studies, and therefore, will be able to test correlations between L-VGCC activity and expression of multiple genes in the same cells. Together, these studies will systematically determine whether the development of some biomarkers of brain aging is modulated by E2 in female and male rats, and will elucidate linkage of functional biomarkers to specific genomic pathways.
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