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A Research Journey With Eric Kandel
From: Columbia University
| By:
Eric Kandel |
EDITOR'S INTRODUCTION |
Eric Kandel (below), who shared the 2000 Nobel Prize in physiology or medicine with Arvid Carlsson and Paul Greengard  for their work on signal transduction in the nervous system, talks about how he came to use a molecular approach in studying learning and memory. Using the nervous system of the sea slug Aplysia, Kandel discovered that synaptic function is important for learning and memory. He also learned that the synapses react very differently with short-term memory than with long-term memory, eliciting a physical change in the synapse itself in the latter case. He talks about how his ideas evolved and how the people he has worked with have influenced his research over the years. |
 he fact that nerve cells connect in a very precise way raises an enormous paradox for the field of learning and memory: How do you reconcile the specificity of these connections with the plasticity of behavior? |
During the course of my research, I began to find that the connections between nerve cells are specified but the strength of the connections is not. Learning and memory modulate the strength of synaptic connections between well-connected cells. At first I tested this in a number of artificial ways, but after a while I realized I needed to work out a complete behavior in some detail. I recruited a colleague and we began working out the first detailed neurocircuitry of behavior. We saw that as we modified the behavior of animals in simple ways, we could see the specific connections that make up this neural circuit change. |
While we were doing this, another very fortunate thing happened to me. I bumped into Jimmy Schwartz, a professor of physiology and cellular biophysics at Columbia University, who was a very good friend from college and medical school. He had been doing biochemistry at Rockefeller University and said that he had been speaking to someone in neurobiology there who told him to speak to me because the nervous system of Aplysia (a cold-water sea slug) might be good to study from a biochemical point of view. Jimmy came to see me and we began a wonderful collaboration that continues to this day. |
He and I soon discovered that the second messenger system, cyclic AMP-protein kinase A, which had been discovered a few years earlier, was one of the important systems that was modulated. I think Jimmy and I were the first ones to begin looking at what cyclic AMP does in a detailed, functional sense, and we were doing this in the context of learning and memory. It was really fantastically exciting. He and I began to explore some of the biochemical mechanisms that underlie these changes in synaptic strength. |
Then, naturally, a number of opportunities evolved. We initially began by looking at the short-term changes in the brain. But obviously what is really fascinating about memory is how long-term memory is stored. Here we were doubly fortunate. I began to collaborate with Craig Bailey, associate professor of neurobiology and behavior at Columbia, who soon showed that long-term memory was different from short-term memory in giving rise to the growth of new synaptic connections. Short-term memory involves covalent modifications of pre-existing proteins producing transient changes in pre-existing synapses. Long-term memory involves the growth of new synaptic connections. |
Just then we recruited Richard Axel, who is currently the Higgins Professor of Biochemistry and Molecular Biophysics and a professor of pathology. Richard and I had become friends in 1977 or 1978 and he and I had been recruited for the Howard Hughes Medical Institute. We were on some ad hoc committee here at Columbia and we were walking along on the university campus one day. In a typical Axel conversation, he said, "I am thinking of doing something in the brain. I am getting tired of what I am doing. I think I am going to do the neurobiology of walking." I said, "Richard, that is not a problem that is very accessible to a molecular approach." |
But we began to talk, and he influenced me an enormous amount. One of the people in his lab got interested in trying to adopt a molecular approach to the nervous system. I think he and I were the first to really use molecular methodology--his methodology--to begin to approach problems in the brain. That got me to think even more in molecular terms. |
I began to think of how long-term memory is set up. Through a number of really marvelous postdoctoral fellows, we discovered that long-term memory is different from short-term memory in requiring the turning on of genes. Gene transcription is involved--we could identify a number of the key transcription factors such as CREB (cAMP response element-binding protein), including repressors of long-term memory. So we made a really interesting convergence: When you put something in long-term memory, not only do you have to activate a transcriptional system, you have to remove a repressor. It makes me wonder what kinds of mutations people have who can read a book once and never forget a page of it. |
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