Project 2 - Aging is associated with a decline in cognitive performance. PFC shows particularly largefunctional deterioration with age. The molecular mechanisms responsible for this decline are poorlyunderstood. Our preliminary data suggests that aging is associated with increased cAMP signaling in thePFC. Antagonizing cAMP signaling in the PFC improves working memory performance and increasing cAMPsignaling in the PFC causes further declines in working memory. We have also shown that HCN1 and 2channels are expressed on dendritic spines where cAMP can affect channel opening and reduce themagnitude of synaptic inputs. Aged PFC shows reduced expression of RNA for PDE4A which would beexpected to cause increased cAMP levels. Western blots demonstrate increased HCN1 expression in agedPFC. We hypothesize that cAMP levels increase with aging and that the deleterious effects of cAMP aremediated by HCN ion channels. To test this hypothesis we will measure cAMP levels in the prefrontal cortexof young, aging, and aged rats. We will then overexpress PDE4A using viral methods and measure workingmemory performance. We predict that increasing PDE4A expression to that seen in young animals willimprove working memory performance in aged rats. We will then examine the role of HCN channels byoverexpressing or knocking down HCN 1/2 expression and measure working memory. We predict thatreducing HCN expression will reverse the effects of aging on PFC function and that overexpression willcause further deterioration. We will use cDNA microarrays and protein profiling approaches to examine RNAand protein expression changes associated with aging in the PFC to generate additional hypotheses. Genesidentified in this manner will be targeted for overexpression and knockdown studies. We believe that thiswork will identify components of the cAMP signaling pathway that underlie decreased working memoryperformance associated with aging. Lay language: Certain cognitive capacities become less efficient withaging. One such capacity known as working memory plays an important role in carrying out tasks associatedwith daily living and is mediated by the prefrontal cortex. We have determined that age-related changes incyclic AMP signaling in the prefrontal cortex may cause reduced working memory performance. Thisproposal seeks to uncover the molecular mechanisms responsible for these changes.
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