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Mighty Mice Stay Smarter Longer

BU profs find genetic boosts offset memory loss in old age

A genetically enhanced “smart” mouse outperforms normal mice in this memory test. Photo courtesy of CSN

You don’t have to be human to have senior moments. Experiments have revealed that animals of all sorts show declines in learning and memory as they age. But Boston University researchers, using genetically engineered mice and working with an international team of neuroscientists, have discovered a protein that might help keep those old minds sharp.

Specifically, the researchers, including a team from BU’s Center for Systems Neurobiology (CSN), focused on a brain protein called NR2B.

The protein stimulates a receptor in the hippocampus, a region of the brain known to be important for learning and memory in many species, allowing it to more efficiently process the signals of neurotransmitters.

A few years ago, the researchers genetically engineered some mice to make higher levels of this brain protein, creating “smart” mice that consistently outdid their normal counterparts in tests of learning and memory. In follow-up research published in the March 2007 European Journal of Neuroscience, they show that the cognitive advantage of the genetically enhanced mice continues into old age (about 15 to 18 months for a mouse).

The most recent research began with a physiological puzzle: if NR2B were so helpful to brain function, then why, as previous experiments had shown, did the brains of many animal species start producing less NR2B at the beginning of sexual maturity? After all, says Joe Tsien, a School of Medicine professor of pharmacology and experimental therapeutics and CSN director, “wouldn’t it be better if we all lived forever and had a superpowered brain?”

One hypothesis was that NR2B introduced calcium into the neurons of the hippocampus and that too much NR2B could allow toxic levels of the mineral to build up in the brain. If that were true, says Tsien, “initially you’d see robust and superior learning and memory” from the genetically altered mice, “but over time you would get brain damage and a loss of that memory function.”

So, Tsien and his colleagues, including scientists from the Shanghai Institute of Brain Functional Genomics and from the University of Chicago, decided to see how well the “smart” mice performed learning and memory tasks as they aged. They put older transgenic mice up against normal mice in five behavioral tests. In one, they looked at how much time mice spent investigating a new toy placed among older toys in their environment, a measure of how well they remembered what was already there. In another, mice placed in a T-maze had to remember which direction they’d turned to reach a chocolate treat, because researchers alternated the reward’s position after every trial. In test after test, the aged mice with increased NR2B outperformed the normal mice.
Tsien says the results counter the theory of a toxic calcium buildup in the brain from NR2B and suggest that a drug that boosts the protein in human brains could “be useful for improving learning and for treating memory disorders.” But, he cautions, “we don’t expect a direct translation from mice brains to human brains.”

And even if human brain interaction with NR2B follows the mouse model, any resulting drug would be years, if not decades, away. In the meantime, Tsien says, the good news is that people who keep their minds active with mental exercise might be able to up their NR2B naturally, because the gene that produces it “appears to be regulated through activity,” meaning “the more you use it, the more you produce.”

Chris Berdik can be reached at cberdik@bu.edu.