The Genius Gene
Posted: Tuesday, December 31, 1996
Researchers uncover the secret to memory and learning in mice. Does it have the same effect in humans?
Most mice have lousy short-term memories. Put them in a cage with objects they saw just yesterday and the mice will inspect the blocks or toys as if they are brand new. But in a lab at Princeton University, Joe Tsien tests some mice the are a bit more like elephants—even five days after seeing an object for the first time, these non-descript brown mice remember it well enough to ignore as neither food nor foe.
Tsien's mice are not natural talents. They have been genetically engineered to be smarter. By adding a just single gene, researchers greatly enhanced the mouse's learning ability and memory. The gene codes for a communication channel in the brain that seems to be the master key to the brain's gateway for memories and learning experiences.
For the past years, it has been the declared goal of Tsien's lab to find the cellular and molecular mechanisms of how memories are stored in the brain. The researchers knew from previous research that a sub-unit of the communication channel played a role in the ability of brain cells to interact. Presumably, interconnections form as memories are stored in the brain, a flexibility that is typical for juvenile brains.
To test the role of the receptor, called NMDA, Tsien and co-workers engineered mice that lacked the gene that codes for that sub-unit. The resulting mice were rather stupid, incapable of remembering a platform submerged in murky water even after a short time, although it was always in the same place. But researchers couldn't prove the channel actually made mice smarter until they reversed the experiment.
The new results, published in the September 3 issue of Nature, obliterates any remaining doubt that the receptor is one of the key switches in the mechanism of memory and learning, says Tsien. The receptor is located strategically at the synapse, the spot where two brain cells meet and communicate. It works like a door: a signal molecule rings the bell and the receptor opens up to let in messengers—electrically-charged calcium atoms in this case. The calcium initiates an electrical pulse that relays the message to other synapses at the opposite end of the brain cell.
In the transgenic mice, the genetically modified sub-unit keeps the door open longer and lets in more messengers to make sure the message does not get lost on the way. And the effect does not wear off over time, so the mice are both unusually smart and retain an elastic juvenile memory. This inspired the researchers to name them "Doogie", after the precocious TV doctor in "Doogie Howser, M.D."
The "Doogie" mice performed better than normal mice in a range of behavioral experiments. They remembered familiar objects up to five times longer than normal mice. They also remembered receiving a weak electrical shock longer, and learned faster to associate it with a sound. Tsien believes this is an important finding: in both mice and men, memories of places or objects and memories of emotions, such as pain, are stored in different parts of the brain. "The mechanisms underlying emotional and rational learning may be the same. We see that (in mice) this receptor affects both," says Tsien.
The receptor also exists in humans, and it is possible that it plays the same role. If so, pharmaceutical companies may some day find a small molecule they can pack into a pill that can modify the channel's properties—or even the activity of the gene itself. Advances in gene therapy technology may make it possible to deliver the chunk of gene directly to the part of the brain affected by memory loss. The most controversial option may be the manipulation of embryos to create genetically-modified geniuses. "We have to be extremely careful to be starting this kind of adventure," Tsien says. In any case, an actual therapy for people's mental abilities is far off. "It's not like tomorrow you're gonna have something," he says.
But Tsien adds, "The question isn't whether we can do it, but it's whether and when we should do it." http://www.molbio.princeton.edu/
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