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EVANSTON, Ill. ‹ In a study published in the June 20 issue of the Proceedings of the National Academy of Sciences, researchers at Northwestern University report new insights into the biological and molecular underpinnings of learning and memory.
Past research has shown that a growth-associated protein, called GAP-43, that is found in neurons and no other organ of the body, is required for the growth of nerve cell processes during the brain's early development and later during neuronal regeneration. What was not known was whether or not GAP-43 could alter axonal growth and synaptic change, elements crucial to learning and memory.
Now, a research team led by Aryeh Routtenberg, professor of psychology, neurobiology and physiology, has demonstrated that GAP-43, when overexpressed in a phosphorylatable form, enhances learning and memory in the mammalian brain. The findings could provide a novel target for new drugs to combat memory loss and learning disorders.
"This is the first evidence that demonstrates that GAP-43 does indeed regulate learning," said Routtenberg. "It does so by accelerating the rate at which learning occurs. Our findings specify the particular sequence of chemical reactions that are involved in the process of storing information."
Routtenberg and his team have demonstrated that genetically engineered mice that have more phosphorylatable GAP-43 in their brains learn tasks more quickly and can forget one strategy in order to learn a diametrically opposed strategy. Experiments also showed that mice overexpressing a form of GAP-43 that could not be phosphorylated had no learning enhancement.
Phosphorylation is a fundamental molecular process in which a phosphate is transferred to a protein, causing the protein to change shape and function. In the case of GAP-43, the protein kinase C (PKC) is the enzyme responsible for its phosphorylation.
The researchers first studied four different types of mice and their ability to learn by putting them through a battery of tests. The tests of spatial and working memory became increasingly complex, requiring the mice to learn from earlier tests in order to locate food in an eight-arm maze.
One strain of mice, called WT, had the normal GAP-43 found naturally in the mouse brain. The three genetically engineered strains had different forms of overexpressed GAP-43, in addition to the normal GAP-43. These included a form that is phosphorylatable (called GPhos), a form that is permanently phosphorylated (called GPerm) and a form that cannot be phosphorylated (called GNonP).
The overall results showed that the GPhos mice were dramatically more adept at accomplishing their tasks in a shorter period of time than the other mice, and, in fact, performed better as the task got more difficult. At the same time, the GNonP mice demonstrated difficulty in performing their tasks.
"The genetic difference between the smart mice and the slower mice, who are unable to phosphorylate GAP-43, is just one base pair in its DNA," said Routtenberg. "This is a dramatic example of how a mutation can have a significant impact on the ability of an animal to learn."
Next, Routtenberg and his team wanted to determine if there were actual differences between the mice in their neural networks involved in the memory process. This required measuring the mice's long-term potentiation (LTP), a model of memory based on the strengthening of connections between nerve cells.
Results showed that the GPhos and GPerm mice, the ones with phosphorylatable GAP-43, had enhanced LTP following the learning and memory tests. The researchers concluded that communication among brain cells is altered during learning and that this, in turn, helps the formation of neural networks that are required to store information, learn and remember.
"It may be the case that GAP-43 works in some ways like insulin," said Routtenberg, "facilitating the metabolic process, accelerating synaptic communication and increasing the rate at which memory is stored. This has important implications for learning."
The researchers are now moving on to the next question. Do normal mice that learn more quickly have more GAP-43 in the learning and memory areas of their brains? That is the subject of a new set of experiments now under way.
Other authors on the paper are Isabel Cantallops, Sal Zaffuto, Peter Serrano and Uk Namgung, from Northwestern University.
The research was supported by the Whitehall Foundation and the National Science Foundation.
(Note to reporters: To receive a copy of the paper, contact the Office of News and Public Information at the National Academy of Sciences at 202-334-2138.)
6/19/00