Another mouse that may someday lead to an interesting drug was recently negotiating a radial maze on the ninth floor of a laboratory at Columbia University, where researchers working with Hughes investigator Eric Kandel have been trying to tease apart the differences between short-term and long-term memory. They do this by testing how mice with specific mutations perform in various mazes.

In this particular case, Gael Malleret, a graduate student, has just placed a small brown mouse at the hub of an eight-armed maze, each arm leading out like spokes from the center and ending in a small dimple in which a sugar pellet had been placed. "The only way for the mouse to remember," Malleret explains, "is to create a spatial map."

"Do you have a smart mouse here?" asks Rusiko Bourtchouladsze, one of Malleret's colleagues.

In the age of sophisticated genetic manipulation, it's a question that has to do with biology as well as learning ability, since researchers have found that laboratory animals' performance in learning and memory can sometimes be altered by modifying a single gene. The mouse the scientists are watching in the maze may be a mutant in which a brain protein has been deleted, but Malleret doesn't know; in blind experiments such as this one, where researchers want to see if a gene deletion affects short-term memory, even the experimenter is kept from knowing whether he or she is testing a mutant or a control animal.

"I'm going to open the gates," Malleret explains, "and the mouse is going to visit each arm of the maze to get the food. So if he visits the same arm twice, it is scored a failure." While a computer tracks the path, speed, and elapsed time of each rodent sortie, the mouse does well for the first five or six arms, but then its memory begins to fail. It revisits two arms previously explored. "Uh oh," says Chris Pittenger, who is also looking on. "Stupid mouse!"

For years, the Kandel group has focused on the biological changes that accompany the transition of a short-term memory (one lasting a day or two) to a long-term memory (one that an animal can recall days or weeks later). Kandel shared the 2000 Nobel Prize in Physiology or Medicine for this work. The effort began in a marine mollusk known as Aplysia, but the growing ability to modify genes in mice has afforded a look at more complex mammalian biology. In addition to studying mechanisms of memory, the team has started using mice to explore several forms of human mental retardation, including Down syndrome and fragile X syndrome.

In mice, the key event in converting a short-term memory into some kind of permanent record is the synthesis of new proteins, probably as a way of physically altering synapses. The mechanism involves a pair of molecules known as CREB-1 and CREB-2, one of which activates the formation of long-term memory while the other represses it.

Tim Tully and his group at Cold Spring Harbor Laboratory have shown that by increasing the amount of the activator, CREB-1, they could create fruit flies with supermemories in learning tasks; Kandel's group showed that by decreasing the amount of the repressor, CREB-2, they could similarly improve animals' memory. "Tully's studies and our studies," says Kandel, "first made us realize that this protein synthesis step is highly regulated and suggested that defects in the system could suppress memory storage."

Although Kandel began to experiment with mice around 1992, he has kept his eye on human beings as well. "There is very good reason to believe that there is a separate syndrome in aging that reflects itself as a weakening of memory but that can be distinguished from Alzheimer disease," says Kandel. "It's called benign senescent forgetfulness, or age-related memory loss, and it often begins around age 40 or 45. There's a drop in memory, but it's not associated with massive cell loss. So we became interested in seeing if we could characterize this in the mouse."

The mice cooperated fully. Kandel's group discovered that even in rodents, memory loss begins in middle age; only 10-15 percent of 3-month-old mice show memory deficits, while 40 percent of 12-month-olds and 80 percent of 18-month-olds display memory flaws.

The declines in performance parallel a significant drop in an activity called long-term potentiation (LTP) in the hippocampus, a central structure of the brain that appears crucial to long-term memory formation. Mary Elizabeth Bach and Min Zhuo in Kandel's group ultimately linked the memory deficits to decreases in dopamine. Indeed, giving dopamine to the animals reversed the memory loss. "So," says Kandel with a laugh, "if you're a mouse, we can help you."

— Stephen S. Hall

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A small brown mouse in an eight-armed maze may help Eric Kandel identify genes that are involved in mental retardation and loss of memory.

Photo: Christopher Denney

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