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12/05/1996 08:00:00

Neuroscientists Single Out Brain Enzyme Essential To Memory and Learning

PASADENA— Researchers have singled out a brain enzyme that seems to be essential in memory retention and learning.

The enzyme is endothelial nitric oxide synthase (eNOS), and is found in microscopic quantities near the synapses, or nerve junctions. In today's issue of Science, California Institute of Technology neuroscientist Erin Schuman, her colleague Norman Davidson, and their six coauthors write that the gas nitric oxide (NO) produced by eNOS has been demonstrated in rat brains to be crucial for "long-term potentiation," which is the enhancement of communication between neurons that may make memory and learning possible.

"This study shows how memory may be stored by changing the way neurons talk to one another," says Schuman, who has worked for years on the role of chemical messengers in learning and memory.

In short, the chemical signals interchanged between neurons during memory formation somehow make future signal transmissions occur more readily. Whatever the precise chemical nature of the exchange, Schuman says that there is a feedback mechanism at the basis of long-term potentiation—a "retrograde messenger" likely to be NO—and that this messenger is what makes learning and long-term memory possible.

Scientists have known for some time that the gas nitric oxide is important in certain physiological processes, says Schuman. Further, her own work in the last couple of years has shown that long-term potentiation can occur even when neurons are not directly connected to one another, presumably because NO is a gas that can diffuse between neurons. Evidence has pointed to nitric oxide as a component in this mechanism despite the fact that rats with a defective gene for manufacturing a closely related form of nitric oxide synthase known as nNOS have no problems with long-term potentiation.

The new study shows that eNOS, however, is crucial in the mediation of signals between neurons. The authors demonstrated this by manipulating a common virus in such a way that it performed like a "Trojan horse." The region of the virus responsible for illness was eliminated, and the gene inserted into the virus was chosen for its action on brain chemistry. The virus infected the neurons and forced the cells to manufacture the protein encoded for by the inserted gene.

One viral construct blocked the function of eNOS in the hippocampus of the rodents, while another restored the eNOS function. The end results showed that eNOS is crucial for long-term potentiation.

Schuman says that while there is no immediate application for the finding, the greater molecular understanding of how brain cells change their properties is an important basic result in itself. Too, the use of viral vectors in understanding brain chemistry is a new approach, and somewhere down the line might be considered as a strategy for gene therapy.

"This gives us a good idea of a model for how brain cells change during learning," Schuman says.

Also involved in the work are Caltech neuroscientists David B. Kantor, Markus Lanzrein, Gisela M. Sandoval, W. Bryan Smith, S. Jennifer Stary, and Brian M. Sullivan.

Written by Robert Tindol