Up-regulation of α1D Ca channel subunit mRNA expression in the hippocampus of aged F344 rats

There is growing evidence that alterations in calcium (Ca²⁺) homeostasis may play a role in processes of brain aging and neurodegeneration. There also is evidence that some of the altered Ca²⁺ homeostasis in hippocampal neurons may arise from an increased density of L-type voltage sensitive Ca²⁺ channels (L-VSCC). In the present studies, we tested the possibility that previously observed increases in functional L-VSCC with aging might be related to up-regulated gene/mRNA expression for Ca²⁺ channel subunits. A significant aging-related increase in mRNA content for the α_1D subunit of the L-type VSCC was observed in hippocampus of aged F344 rats (25 months old) relative to young (4 months old) and middle-aged animals (13 months old), as assessed by both in situ hybridization analyses (densitometry and grain density) and ribonuclease protection assay (RPA). In RPA analyses, the α_1C subunit mRNA also showed a significant increase in 25-month-old rats. No age changes were seen in mRNA for the β_1b subunit of VSCC or for GAPDH, a standard control. The clearest increases in α_1D mRNA expression were observed in subfield CA1, with little or no change seen in dentate gyrus. Although these results alone do not demonstrate that mRNA/gene expression changes contribute directly to changes in functional Ca²⁺ channels, they clearly fulfill an important prediction of that hypothesis. Therefore, these studies may have important implications for the role of gene expression in aging-dependent alterations in brain Ca²⁺ homeostasis.