Dusan Bartsch, a postdoctoral fellow working with Kandel, has extended the mouse work to Down syndrome. Children with this common form of mental retardation inherit an extra copy of chromosome 21, and if they live to the age of 30, they have a greatly increased likelihood of developing early-onset Alzheimer disease. Other researchers had shown that the disease seemed tied to a small piece of the extra chromosome, a piece containing about 50 genes. When studies homed in even closer, it became clear that one gene in particular, the gene for minibrain kinase, was enough to produce a learning deficit in mice.

In talking to parents of children with Down syndrome, Bartsch realized that the retardation seems mild during the first six to eight months of life; therefore, it may not be fully developed at birth. Furthermore, extensive training can sometimes override the defect. So Bartsch created a mouse that models this genetic situation: It overexpresses, or produces unusually large amounts of, minibrain kinase after birth. "When you give mice either of two different spatial tasks," says Kandel, "it's clear that you get a learning deficit with extra amounts of this one gene, and the deficit can be partially overridden by extensive training." Bartsch and his colleague Susan Patterson have also shown that these mice have a deficit in LTP, which can be overridden with training.

A Small Window of Time
These mice suggest both that a drug which shuts off the minibrain kinase might be a form of therapy and that there may be a small window of time after birth when such a treatment could be extremely effective.

The availability of knockout mice and other sophisticated molecular tools has transformed the study of memory, says Kandel. "In 10 or 15 years, one problem—the molecular mechanisms through which memories are stored at any given site—may be solved," he says. "But that will still leave the systems problems. How does the hippocampus interact with the neocortex [the thinking part of the brain] to produce memories, and how do emotions from the amygdala enter in? That's going to interest people well into the next millennium. Not the one we've just begun—the next millennium."

— Stephen S. Hall

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