Skip to content ↓

Gene, Learning Deficit Linked in Mice

Three research groups-the principal one headed by Nobel laureate Susumu Tonegawa of the Howard Hughes Medical Institute (HHMI) at MIT-have reported the discovery of a specific link between a particular gene and a learning deficit in mice.

The link, the first of such specificity discovered in mammals, sheds new light on the molecular mechanisms of learning and memory. The work, reported in two papers published in the July 10 issue of Science, is also expected to be of value in the treatment of epilepsy, chronic anxiety and strokes.

"This interplay between gene and function might unravel some of the daunting but impenetrable mysteries of the brain," said Alcino J. Silva, postdoctoral fellow at the MIT Center for Cancer Research, the lead MIT author, in a comment to the MIT News Office. Dr. Silva works in the laboratory of Professor Tonegawa, a professor in the Department of Biology. Their colleagues in the work were Yanyan Wang and Charles Stevens of the HHMI at the Salk Institute, LaJolla, Calif., and Richard Paylor and Jeanne M. Wehner, University of Colorado.

Dr. Stevens, a neurobiologist, commenting on the work for the MIT News Office, said that while the results being reported were clearly in the realm of pure science, "there are some interesting correlates that may have clinical implications soon, and this is the reason that you have to do basic research, because clinical applications pop up in places you least expect them."

It is an exaggeration of the learning mechanism-an event known as excitotoxicity-that causes the death of many brain cells in a stroke, he said. "The cells literately excite themselves to death. And the mechanism involved when this occurs is the very subject of our studies, long term potentiation. So the knowledge we develop may lead to changes in clinical applications that will help stroke and trauma victims recover."

Dr. Wehner, associate professor at the Institute for Behavioral Genetics at the University of Colorado, made this comment about the group's work: "Understanding the regulation of general cognition is an enormous task, so we chose to focus specifically on spatial learning which involves the ability of an organism to find precise locations in a complex environment and is regulated by certain brain structures. The use of the technology employed in our studies allows identification of proteins in those brain structures that are essential to spatial learning and memory processes. Although our findings at this time are not directly applicable to human disease states and learning disabilities, the continued study of complex learning using animal models will ultimately result in the understanding of the many physiological and biochemical steps that occur in memory formation."

Using a recently developed genetic engineering technique that allows the elimination of a specific gene or genes, the scientists deleted the alpha CaM kinase II gene from mice. The gene encodes a molecular component of the hippocampus, a brain structure believed to be involved in learning and remembering complex information, for example, the relative location of objects in space.

In contrast with normal mice, those with the engineered genetic lesion were unable to learn the location of objects in space in a well-known behavioral test, the water-filled Morris maze. Mice without the lesion learned quickly how to negotiate the maze and retained the information, the scientists report in the papers published in Science.

The maze has transparent sides and mice learn to negotiate it by using objects in the room outside the maze as guideposts. In one test, mice had to swim to a hidden platform in the maze. The only way they could know their position relative to the platform was by the spatial relationships between objects outside the maze. The mutant mice had a much more difficult time finding the platform than the normal mice did.

The reason the genetically altered mice were unable to learn what normal mice can, the scientists said, is that the cells of the hippocampus of the altered mice lacked long term potentiation (LTP), the ability to stabilize cell-to-cell transfer of information.

The researchers said that scientists have suspected for some time that learning initiates changes in the strength of the connections among brain cells that process the information to be remembered. The changes leave an imprint on the networks those cells form.

In the genetically engineered mice, changes in the pattern of communication among brain cells last only minutes, instead of the much longer periods observed in normal mice and other mammals including humans, the researchers reported.

"Thus, these studies strongly suggest that these stable changes in the pattern of communication among cells (LTP) might indeed be the underlying mechanism of memory storage in the brain," Professor Tonegawa said.

The scientists were surprised that deleting the gene resulted in such a specific disorder, they said.

"This specificity confirms that the approach that we initiated promises to have wide applications for the study of brain function, since it implies that the manipulation of single genes encoding molecular components of the brain may result in very specific disorders that can then be correlated with the specific molecular lesion generated."

It is this interplay between gene and function that the scientists hope will reveal some of the mysteries of how the brain functions.

The molecular components that regulate the LTP process are believed to be involved in epilepsy. "The electrical storms that rage during seizures in the epileptic brain might be due to an abnormal increase in the facility with which brain cells communicate, so that normal stimuli get abnormally amplified in these epileptic networks of cells," Professor Tonegawa said. "Since these mice lack LTP because they do not have the alpha CaM kinase II gene, it follows that drugs that modulate the activity of the alpha CaM kinase II molecule might also be useful for the control of seizures."

LTP might also be involved in chronic anxiety because the process of learning to fear some things, but not others, in the environment is also thought to be dependent on changes in connections between cells in certain regions of the brain. The scientists report that the altered mice appear to be unable to stop fearing common stimuli in their environment.

In humans, chronic anxiety is extremely debilitating and there are few effective drug treatments. "These mice may provide a means to test drugs against this disorder, and our finding that the alpha kinase II gene might be involved will target drug design to those compounds that might directly or indirectly modulate its function," Dr. Silva said.

A version of this article appeared in the July 15, 1992 issue of MIT Tech Talk (Volume 37, Number 1).

Related Topics

More MIT News