Sci. Aging Knowl. Environ., 12 November 2003
Vol. 2003, Issue 45, p. nw152
[DOI: 10.1126/sageke.2003.45.nw152]


The Many Ways of Forgetting

Sharpening long-term memory in the elderly might blur their short-term recall

Mitch Leslie;2003/45/nw152

Key Words: Sp-cAMPS • Rp-cAMPS • rolipram

If you walk into a room but suddenly forget why, a different brain area falters than when you fail to recognize the cashier at JCPenney as your senior prom date. The two regions not only stow different information, but they age differently, according to a new study. The work shows that prodding a pathway crucial for memory evokes opposite responses in the two regions, suggesting that drugs under development to spur long-term recall in older folks could hinder other types of remembering.

The brain area called the hippocampus etches durable memories, such as how to get home along an oft-traveled route. But another part of the brain, the prefrontal cortex, manages working memory, which holds in mind facts needed temporarily. Like our jowls and abs, both brain areas get flabby with age. Neuroscientists blame the hippocampus's decline on waning activity of a biochemical pathway called cAMP/PKA, which strengthens connections between nerve cells. Dosing rodents with compounds that incite the pathway improves long-term memory, whereas inhibitors promote forgetting. The promise of these molecules to perk up flagging long-term memory has spawned two biotech start-ups involving Nobel laureates. But 4 years ago, neuroscientist Amy Arnsten of Yale University School of Medicine and colleagues raised the caution flag by showing that a cAMP/PKA-stimulating compound saps working memory in young rats. Her team wanted to find out whether nudging the pathway exerts the same effect on older animals.

The researchers gauged working memory by training young and old rats to navigate a maze. The weaker an old rat's working memory, the worse it became after treatment with a molecule that excites the cAMP/PKA pathway. Infusing the rodents with a cAMP/PKA inhibitor produced the opposite effect: Elderly rats with feeble working memory improved. Neither compound boosted working memory in young animals or in maze-savvy old animals. Spurring the pathway coaxes PKA to affix a phosphate group to another molecule called CREB. To confirm that cAMP/PKA activity surges in the aging prefrontal cortex, the researchers measured the number of hippocampus cells toting tagged CREB in young and old animals. Old rats carried one-third more such cells than did youngsters. Although the pathway slows with age in the hippocampus, the new results suggest that it cranks up in the prefrontal cortex, says Arnsten. A hyperactive pathway might fuddle working memory by preventing the brain from erasing obsolete information, she speculates.

"The study smashes the incorrect assumption that anything that enhances hippocampal memory is positive for memory overall," says neuroscientist Peter Nguyen of the University of Alberta School of Medicine in Edmonton, Canada. The results warn that researchers won't be able to develop "a single magical memory-enhancing drug," he says. However, neurobiologist Ted Abel of the University of Pennsylvania in Philadelphia proposes that scientists could devise a drug with opposite effects on the cAMP/PKA pathway in the hippocampus and the prefrontal cortex. While researchers work out the biochemical subtleties, the rest of us will have to stick to our low-tech mnemonics: parking in the same spot every day and using plenty of Post-it notes.

--Mitch Leslie

November 12, 2003
  1. B. P. Ramos et al., Dysregulation of protein kinase A signaling in the aged prefrontal cortex: New strategy for treating age-related cognitive decline. Neuron, 5 November 2003 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: M. Leslie, The Many Ways of Forgetting. Sci. Aging Knowl. Environ. 2003 (45), nw152 (2003).

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