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In Brain, One Gene is Worth a Thousand Words

For release: Tuesday, February 20, 2007

Using microarray technology, researchers supported by the National Institutes of Health (NIH) have shown that people with one variant of a gene that is active in the brain have better episodic memory – the ability to remember events and facts – than do people without that variant.  The researchers are using the same technology to identify genetic risk factors associated with neurological diseases.

“This is a paradigm that everyone will be using to dissect human disorders,” said Dietrich Stephan, Ph.D., a lead author on the study and a senior investigator at the Translational Genomics Research Institute (TGen) in Phoenix, Arizona.  TGen is a member of the NIH Neuroscience Microarray Consortium, a group of labs supported in part by the NIH Neuroscience Blueprint to advance microarray – or “gene chip” – technology, and make it more widely available to the scientific community.

In the study, published in Science,* Dr. Stephan and his colleagues tested about 1000 people from the U.S. and Switzerland for their capacity to memorize sets of words, and divided them into four equal-sized groups based on their performance.  They then collected DNA from each group, and scanned it for more than a half million single nucleotide polymorphisms (SNPs) – sites where the genetic code differs from one person to the next, usually with no apparent effect. 

Just one SNP in a little known gene, previously named Kibra because it’s active in kidney and brain, was reliably linked to differences in episodic memory.  People in the two groups that scored most poorly on the memory tasks tended to have one version of Kibra, while people from the two top-scoring groups tended to have another version – the “T allele.”

In other experiments, the researchers retested carriers and non-carriers of the T allele on a set of memory tasks while using functional magnetic resonance imaging (fMRI) to visualize the level of activity in their brains.  Non-carriers of the T allele showed increased activity in the hippocampus – a brain region important for learning and memory – suggesting their brains had to work harder on the tasks.

Using microarray technology allowed Dr. Stephan and his team to conduct “an unbiased screen of the genome” rather than guessing about which genes might be associated with memory, he explained. 

A microarray is a chip of glass coated with thousands of DNA fragments, with each one’s position on the chip precisely charted.  The microarrays used by Dr. Stephan were coated with just over 500,000 pieces of human DNA containing distinct SNPs.  After collecting DNA from the study participants, the researchers tagged it with a fluorescent chemical and washed it over the chip.  SNPs in the participants’ DNA stuck to matching SNPs on the chip, lighting up like blips on a tiny radar screen.

“We’re using this exact approach [to search for SNPs] in probably 25 different neurological disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, and bipolar disorder,” Dr. Stephan said.

Meanwhile, he and his colleagues continue to study Kibra and other possible memory-related genes.  In experiments on aged rats, TGen researchers have found drugs that appear to enhance memory by acting through Kibra, he said.  Also, in ongoing microarray experiments, they’re searching for genes related to different types of memory, such as procedural memory – which dictates our ability to remember how to do things like ride a bike.

Although Dr. Stephan acknowledges that a Kibra-based “memory pill” would have widespread appeal – think weary college students – his research is focused on memory in disease and aging, he said.

“We study memory in the general population to gain insights into memory impairment,” he said.  “All of us eventually go down that path where we start forgetting important people and events in our lives.”

The NIH Blueprint is a framework to enhance cooperation among the NIH Office of the Director and the NIH Institutes and Centers that support neuroscience research.  The Blueprint enables member Institutes and Centers to plan initiatives that cut across diverse areas of neuroscience, to develop research tools of broad utility, and to create unique interdisciplinary training opportunities for neuroscientists.

*Papassotiropoulos A, Stephan D, et al.  “Common Kibra Alleles Are Associated with Human Memory Performance.”  Science, October 20, 2006, Vol. 314, pp. 475-478.

-By Daniel Stimson, Ph.D.

Last Modified February 21, 2007