Up-regulation of α1D Ca2+ channel subunit mRNA expression in the hippocampus of aged F344 rats

doi:10.1016/S0197-4580(98)00099-2

Neurobiology of Aging

Volume 19, Issue 6, November–December 1998, Pages 581-587

https://doi.org/10.1016/S0197-4580(98)00099-2 Get rights and content

Abstract

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.

Section snippets

Subjects

Subjects were male Fischer-344 (F344) rats acquired from the National Institute on Aging-sponsored colony at Harlan Sprague–Dawley (Indianapolis, IN). Upon arrival, rats were housed in individual cages in an isolated colony reserved for specific-pathogen-free animals. All rats had ad libitum access to food and water, and were maintained on a 12:12 h light:dark cycle. Rats were either 4 (young, n = 12), 13 (middle-aged, n = 12) or 25 (aged, n = 12) months old when euthanized by rapid

Results

A number of individuals in the aged group showed gross pathologies that are commonly associated with the aging process in the F344 rat strain. Included were splenomegaly (8 out of 12 animals), testicular hypertrophy (6 out of 12 animals), and pituitary tumors (2 out of 12 animals). There was no correlation between pathology and age-related changes in mRNA expression in individual animals. Animals with pituitary tumors were not included in the data analysis.

Discussion

The results of this study provide direct evidence that mRNAs encoding Ca²⁺ channel-related subunits are increased with brain aging, apparently in a subunit and region-specific manner. Significant increases in α_1D mRNA were preferentially observed in subfield CA1 (Fig. 2), using both densitometric and grain density analysis. However, grain density analysis revealed an increase in CA3 as well, primarily reflecting differences between the middle-aged and aged groups. Significant aging effects were

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Original ArticlesUp-regulation of α1D Ca2+ channel subunit mRNA expression in the hippocampus of aged F344 rats

Abstract

Section snippets

Subjects

Results

Discussion

Curr. Opin. Neurobiol.

Neurobiol. Aging

Trends Neurosci

Neurobiol. Aging

Neurobiol. Aging

Life Sci

Life Sci

Curr. Opin. Neurobiol.

Neurobiol. Aging

Brain Res

Neuron

Brain Res

Brain Res

Cell

Mech. Aging Dev.

Life Sci

Neurobiol. Aging

J. Biol. Chem.

Brain Res

FEBS Lett

Trends Neurosci

Life Sci

Neuron

Neurobiol. Aging

Mol. Brain Res.

Trends Neurosci

Trends Neurosci

Neurobiol. Aging

Normal agingRegionally specific changes in hippocampal synaptic transmission

Trends Neurosci

Hippocampal synaptogenesis in cell cultureDevelopmental time course of synapse formation, calcium influx, and synaptic protein distribution

J. Neurosci.

Long-term changes in synaptic efficacypotential mechanisms and implications

Original Articles
Up-regulation of α_1D Ca²⁺ channel subunit mRNA expression in the hippocampus of aged F344 rats