Genetic Twist Boosts Recall

Skewed distribution. BDNF is distributed differently in cultured neurons with the valine (top row) and methionine (bottom row) variations.

Buried deep with the brain, the sickle-shaped hippocampus plays a key role in learning and memory. Now, researchers have identified a tiny genetic variation that may influence just how effectively an individual's hippocampus functions in at least one type of memory. The variation could possibly also influence a person's susceptibility to brain diseases such as Alzheimer's.

The variation occurs in a protein called brain-derived neurotrophic growth factor (BDNF). Although BDNF has been known to be a general facilitator of neuron growth and maintenance, recent research has also linked the protein to the neuronal changes underlying learning and memory. Now, a team led by Michael Egan, Bai Lu, and Michael Weinberger, at the National Institutes of Health (NIH) in Bethesda, Maryland, has found that a single amino acid change in BDNF--a swap of methionine for valine at position 66--can affect a person's ability to perform a memory task.

In work reported in the 24 January issue of Cell, the team found that at least one of the two BDNF gene copies carries this variation in about 18% of the 600 people they studied. The researchers also showed that people with the methionine variant fared worse on a test that measures so-called episodic memory--the ability to remember experiences. Weinberger and colleagues note that the variant's effect on memory is small: People with it have comparable IQs to those without it, for example. But the findings raise the possibility that people with the variant may be more susceptible to the memory loss that may come with age or injury. “Everybody may not have the same genetic tool box to deal with additional insult,” as Weinberger puts it.

Brain-imaging studies confirmed that hippocampal function was abnormal in people with the methionine variant. (In one test, the activity went up when it should have gone down.) And test tube experiments pointed to a possible reason. Normally, the protein is secreted by neurons when they are stimulated, which is thought to help strengthen synapses. But in cultured hippocampal neurons with the methionine variant, BDNF wasn't transported to the nerve endings as it should be and wasn't secreted when the neurons were stimulated.

The work “provides a very nice demonstration that BDNF plays a role in some forms of human memory,” says neurobiologist Susan Patterson of Columbia University in New York City. Mu-Ming Poo of the University of California, Berkeley, agrees, describing the findings as “a very bold link of a molecular defect with a defect in cognitive function.”

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