Molecular aspects of aging in hippocampal neurons

The study of the molecular mechanisms of brain aging is an exciting but generally poorly understood field. Aging is a multifactorial process and gene expression of many molecules undergo age-related changes. Therefore, it is very important clinically, scientifically and societally to determine how the coordinated alterations of gene expression lead to cell degeneration. The hippocampus represents an ideal model to study the aging process, as it is one of the few brain regions showing early and severe age-related alterations. Given the complexity of patterns of regional gene expression, we have chosen to study the molecular mechanisms of aging within individual hippocampal neurons. In order to study expression of multiple genes simultaneously at the single cell level, the antisense RNA amplification technique was developed as a part of this thesis. This thesis describes the coordinated changes in gene expression within individual hippocampal neurons as a function of aging both in vitro and in vivo. Our data show that in the hippocampal primary culture, gene expression of GABA$\sb{\rm A}$ receptor $\alpha$ subunits and glutamate receptor subunits are selectively changed with age. The composition of these two groups of genes change significantly as a function of time. The in vivo study using acutely cultured hippocampal slices demonstrated selective decreases in the composition of the glutamate receptor family. Additionally, the mRNA of GABA$\sb{\rm A}$ receptor $\alpha$1 subunit and Ca$\sp{2+}$/calmodulin dependent protein kinase II were also decreased. However, the GABA$\sb{\rm A}$ receptor $\alpha$4 subunit mRNA exhibited a significant increase during aging. Type II glucocorticoid receptor mRNA was highly expressed in some pyramidal cells from aged hippocampal slices compared to younger cells. In general, Cu/Zn superoxide dismutase mRNA decreased with age, but increased significantly in the late period of aging. Our findings suggest that multiple gene expression coordinately change within individual hippocampal neurons during aging. Therefore, the interactions among multiple factors are most likely essential for mediating age-related degeneration. These studies may produce a molecular fingerprint of the aged hippocampal cells which could lead to a better understanding of the mechanisms of aging