Mickey's Memory Maximized by Man

By Ellen Kuwana
Neuroscience for Kids Staff Writer
September 22, 1999

September Is Time For School

School has started. You're being bombarded with new information. Concepts to understand. Spelling words to master. In no time at all, you'll be studying for quizzes and tests. Wish you could take a magic pill and learn things faster? Wish you could remember things for longer? Although this sounds like science fiction, it is already happening in laboratory mice. Warner Brother's television cartoon "Pinky and The Brain," in which The Brain is a genius mouse made by Acme Labs, may be closer to reality than you think.

The Big Picture

By manipulating a single gene, scientists have created a genetically engineered mouse that outperforms regular mice on learning and memory tests. The results of this study were reported in the September 2, 1999 issue of the journal Nature. When they received an extra copy of the NMDA receptor gene, the mice were better able to navigate mazes, remember objects, and retain for longer information that they had already learned.


The NMDA receptor is an important molecule. It is the receptor for the neurotransmitter glutamate, an excitatory transmitter in the brain. The receptor is found in many neurons in the brain where it plays a crucial role in synaptic plasticity (the ability for synapses to change) and memory formation, which occurs when learning takes place.

Genetic Engineering

Two basic experiments can be performed to examine what function a gene is affecting. First, scientists can remove the gene or block its effect. This is called gene deletion or "knocking out" the gene.

The other way to analyze a gene's function is to add the gene. This is called gene insertion. In this case, the added gene (NR2B) produces increased amounts of a protein (for the NMDA receptor). The mice produced twice the normal amount of protein, so that the overall activity of the NMDA receptor was enhanced. The study's head scientist, Joe Tsien (pronounced chee-YEN), explained, "It's like trying to open a window to get fresh air. The longer you open the window, the more fresh air you get." In this case, the "air" is the activated NMDA receptors. Activated NMDA receptors help in learning and making memories because they increase the amount of time that messages between nerve cells can last.

Test One: Putting the Mice to the Test

The scientists compared the engineered mice (called transgenic mice) to control mice (regular lab mice). The mice were initially shown two different objects and a few days later they were shown one new object and one of the original objects. The regular mice spent equal time examining both objects, but the transgenic mice did something different: they only examined the new object, suggesting that they "knew" that they had already seen the other object. The researchers interpreted this to mean that they had remembered the old object, but the control mice did not.
Test 1
Training Sessions
Test Sessions

Test Two: Not So Shocking Results

Next, the scientists put the mice in a chamber and gave them small electrical shocks. The shocks were not big enough to hurt the mice, but did appear to frighten them. After getting a shock, the mice were returned to their cages. Sometime later (ranging from one hour to one day), the mice were brought back to the chamber. The transgenic mice showed more fear than the control mice, suggesting that they remembered what had happened to them in that specific place. The researchers then placed the mice in the chamber, shocked them, and played a tone - this made the mice relate the sound to the shock. When the mice heard the tone later, the transgenic mice displayed more fear than the control group, again suggesting that they remembered the association.

Test Three: Quick Learning

The scientists retaught ("reconditioned") the mice to fear the tone by pairing it with the mild shock again. Then they put the mice in the same chamber, but didn't shock them. The transgenic mice were at first more fearful of the chamber, likely because they remembered the shocks, but they also calmed down quicker than the control mice. Perhaps they understood the change in the conditions quicker. This could mean that they learned more effectively.

Test Four: Are these Mice Spatial?

The final test looked at the spatial skills of the mice. A mouse-size pool was filled with cloudy water, with a ramp hidden somewhere in the pool. The goal was to find the ramp: if the mouse found the ramp, it could climb out of the water. It only took the transgenic mice about three "swims" to find the ramp; the control mice required about six tries. A swimming result!

Why So Many Tests?

The various tests demonstrated several aspects of brain function. These experiments show that the mouse brain processes information related to touch, sights, and sounds using a common biochemical pathway that involves the NMDA receptor.

These Mice are Smarter...Or Are They?

News reports have hailed these engineered mice as "smart mice." Tsien himself has used this term. Although their performance on the tests is impressive, "smart" is not really the proper term for the mice. Tests were not done to assess their intelligence. In fact, it would be hard to get two people to agree on a precise definition of intelligence. It is more accurate to say that the mice learned faster and remembered longer, rather than to say they were smarter. People can have poor short-term memories and still be smart. There is no one gene that determines intelligence. Genes and experience influence what we learn and how we learn it.

Conclusions and Cautions

This study suggests that the NMDA receptor is crucial to learning and memory. This receptor is also present in human brains, so perhaps this work will lead to treatment for Alzheimer's disease, or other diseases in which learning and memory are impaired. But don't expect this to happen any time soon. This is just the first step, and a small step, toward improving our ability to learn and retain memories. No one knows the long-term effect of altering the brain's chemistry. The NMDA receptor, for example, lets calcium into brain cells. Too much calcium may make you more apt to have a stroke. A change seemingly as small as manipulating one gene or one protein can have huge consequences.

References and further information:

  1. LISTEN to a real audio Science Friday interview with scientists involved with the "smart mouse" research
  2. "Making Smart Mice," Scientific American, Sept. 7, 1999.
  3. "The Genius Gene," by Beate Kittl, Science News, Sept. 2, 1999.
  4. "Just how smart are these mice?" by Faye Flam, Seattle Times, Sept. 14, 1999.
  5. "Scientists can now make mice smarter," by Richard Saltus, in the Seattle Post-Intelligencer, Sept. 2, 1999, page A6: an excellent description of the role of the NMDA receptor in learning.
  6. "Mickey Mouse, Ph.D." - Scientific American, November 1999
  7. Tang, Y., Shimizu, E., Dube, G.R., Rampon, C., Kerchner, G.A, Zhuo, M., Liu, G. and Tsien, J.Z. Genetic enhancement of learning and memory in mice. Nature, 401:63-69, 1999.

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