Brain Research Links Single Gene to Learning
For the first time, a single gene has been linked to the learning process.
Researchers from the Massachusetts Institute of Technology and the Salk Institute in La Jolla report today in the journal Science that their findings with mice provide insight into the biochemical process by which the brain learns, particularly into how connections between brain cells are strengthened to form memories.
In the study, mice missing the gene for a key brain enzyme were unable to remember how to work their way through a maze. Though this is the first such gene found, the researchers believe there may be others involved in the learning process.
Although the research is directed toward a better understanding of the brain, it may also have implications for human health. Epilepsy, chronic anxiety and damage to brain cells during a stroke are all believed to be caused by aberrations in the same basic process involved in learning, and the discovery may lead to novel ways to treat or prevent them.
“The paper is particularly significant in two ways,” said Dr. Paul Greengard, a neuroscientist at Rockefeller University in New York City. It is important because it implicates one gene in learning and memory, he said. “The ability to remove a single gene from the mice also opens up a whole new way of studying learning and memory,” he said.
“It’s an incredibly fascinating approach,” said neuroscientist Ron Davis of the Cold Spring Harbor laboratory in New York. “Genetics is going to be the best way” to study the biology of learning.
The researchers are studying a learning process called long-term potentiation, or LTP. In this process, thoughts or actions electrically excite specific brain cells, causing strengthening of the connections between the cells. These strengthened connections become stored memories. Indirect studies have suggested that a group of enzymes called kinases play a key role in strengthening those connections and forming memories.
MIT molecular biologists Susumu Tonegawa and Alcino J. Silva used genetic engineering techniques to remove or “knock out” the gene for one of these enzymes, called CAM kinase, from mouse embryos. The knockout mice matured normally, but they exhibited learning problems as adults.
Geneticists Richard Paylor and Jeanne M. Wehner of the University of Colorado tested the animals’ learning abilities in a round tank of murky water known as a Morris maze. A transparent glass platform sits just below the water surface on one side of the tank.
Normal mice placed in the maze eventually find the platform and climb out of the water. During later tests, they are able to find the platform quickly by locating reference points outside the tank--a process known as spatial learning. The knockout mice are unable to remember the location of the platform, indicating that their spatial learning is impaired.
The knockout mice also continued to exhibit a “startle effect” that is normally overcome as mice mature. In the startle effect, the mice fail to remember that objects in their normal environment are harmless and are thus startled every time they encounter them. This produces chronic anxiety very similar to that exhibited by anxious humans, who also fear common objects in their environment, said Dr. Charles Stevens, a Salk neurobiologist.
The researchers believe that these defects in learning ability are a result of the absence of the CAM kinase gene. Some researchers have argued that absence of the gene may produce a more general impairment by interfering with development of the brain during infancy. But an examination by Stevens and Dr. Yanyan Wang of Salk showed no visible abnormalities in the brains. Furthermore, tests on the brain tissue by Stevens and Wang showed that it lacked only LTP.
The findings should promote research on a phenomenon called excitotoxicity, which is the cause of brain-cell death in epilepsy, stroke and head trauma victims. The biochemical mechanisms of LTP and excitotoxicity are apparently identical, Stevens said. It is only the degree of excitation that marks the difference between learning and cell damage. “A little bit (of excitation) and you get LTP. Too much and you kill the cells,” Stevens said.
Studying the knockout mice should help in understanding how these problems occur and make it possible to test new drugs that could prevent excitotoxicity.
Chronic anxiety is also “extremely debilitating” in humans, Silva said, and the mice should be useful for testing drugs for that condition. A team headed by Dr. Eric Kandel, a neuroscientist at Columbia University, has created knockout mice in which a different kinase gene is missing and has obtained similar results.
