Subregion Specific Changes In Immediate-Early Genes in the Aged Hippocampus

Abstract

The normal aging process is accompanied by changes in cognitive function. One of the brain regions known to be an early target of the aging process is the hippocampus, a medial temporal lobe structure that is critically involved in spatial learning and memory function. The formation and maintenance of memory relies on rapid and sustainable synaptic modification, which requires new gene expression. Immediate-early genes are the first genes to be induced following relevant stimuli, and include genes that encode transcription factors, such as c-fos and zif268, and effector proteins that directly influence cellular function, such as Arc (activity-regulated cytoskeletal gene) and Homer1A. Blocking the expression of any one of these genes interferes with memory function, and thus, each of these genes is thought to have a memory enhancing effect. The hypothesis tested here was that aged animals would show a reduction in the expression of memory-promoting immediate-early genes within the hippocampus, and moreover, that these changes in expression would be subregion specific, based on the finding that the dentate gyrus is most vulnerable to the aging process.Potential age-related changes in immediate-early gene expression within the hippocampus was determined under basal conditions and after induction by a simple behavioral task. Of the genes under investigation, only c-fos did not show age-related changes under basal conditions, or following behavioral induction. The remaining genes, Arc, zif268 and Homer1A, each showed subregion specific patterns of change within the hippocampus under basal conditions or following induction (or both). The coordinate expression of immediate-early genes within the hippocampus was also investigated by assessing the extent to which Arc was expressed within the same neurons as c-fos, zif268 or H1a. The coordinate transcription of these genes was not significantly altered in the aged hippocampus, even though changes in the size of Arc and zif268 neural ensembles occurs within the aged denate gyrus.Taken together, these data indicate that age-related reductions in the basal and induced levels of immediate-early genes occur within the hippocampus, and that these changes are subregion specific.