■ Dr. Richard Tsien is the world’s leading authority on the role of voltage-gated calcium channels. Without calcium channels our hearts would stop, we would have no motor skills and, ultimately, no ability to move and no memories.
__ Dr. Tsien’s early research lead to the discovery of several types of calcium channels in heart cells and neurons. These discoveries, once considered controversial, are now widely accepted.
__ After spending much of his early career studying the heart, he was able to bring his knowledge of calcium channels and how they work in the heart to his study of the brain, pioneering research in the mechanisms and roles of calcium channels and their effects regarding cell-signaling pathways. His research on synaptic communication has led to a better understanding of complex signal-processing in the brain and has provided great insight and influence into our understanding of physiology and neuroscience.
__ In 1988, Dr. Tsien founded the Stanford University Department of Molecular and Cellular Physiology. He currently serves as co-director of the Neurosciences Institute at Stanford University, where his is the George D. Smith Professor of Molecular and Cellular Physiology. His laboratory at Stanford researches synaptic transmission, signal transduction and the pathophysiology of calcium channels.
BRAIN WORLD: Much of your work has involved the implications calcium channels have on cell-signaling, and, ultimately, the long-term plasticity of synapses.
RICHARD TSIEN: Calcium channels are very important to people because they support the heartbeat, blood pressure and supporting memory. If you didn’t have calcium channels, all of those things would come to a grinding halt.
In the brain, a different kind of calcium channel is involved in triggering synapses, which are the junctions between nerve cells. The calcium channel has the job of converting an electrical signal into a chemical signal. For example, they take a cell’s electrical impulse, which could be a tiny change in voltage—about a tenth the size of an AA battery, which only lasts about a millisecond, so it is far faster than the blink of an eye— and that impulse sends the signal from, say, your periphery to your spinal cord, to say, “I touched a hot object.”
__ We asked ourselves whether calcium channels could be the seat of memory formation—if a calcium channel lets in a little bit of calcium and releases a little bit of transmitter, wouldn’t it be logical that a stronger calcium channel would lead to stronger neurotransmitters, and stronger neurotransmitters could, in fact, support the theory of the day, that synapses get stronger or weaker? That is actually the basis of real biological human memory.
__ So we set out to find whether calcium channels changed during long-term memory, and we were disappointed to find that memory did not seem to involve a change in the function of the calcium channel, but rather something downstream of that function—mainly the efficiency of neurotransmission itself.
__ But Steven Siegelbaum at Columbia found in certain cases that our original idea was in part correct—that is, that changes in the strength of synapses acting for a very long time are in fact due to a change in the function of the calcium channel in the pre-synaptic terminals.
BW: So does that mean that calcium channels do support memory?
RT: The channels are the very, very critical step that makes memory. If there weren’t any calcium channels, there wouldn’t be any synaptic transmission, and without synaptic transmission it wouldn’t be possible for our modern view of memory to have a basis for operation. So on the one hand, the calcium channels are part of the basic machinery that allows these things to function, like the power cord that goes to your tape recorder has to be plugged in or your tape recorder won’t work. But if I were to say that the power cord were the basis for your tape recorder remembering things, I would be wrong—it is not the memory; memory belongs to the cassette or the USB device. Calcium channels aren’t the most critical basis of memory, but a more general basis, like a housekeeping sense. In the sense that the power cord is needed for your tape recorder.
BW: Memory, to most people, is a broad concept, a philosophical concept. Could you define what memory is?
RT: We can talk about memory on a lot of different levels: One is your memory of an old friend you haven’t seen for 20 years, or your memory of your first kiss. There are many wonderful and evocative examples of memories that we all experience. On the other hand we could be talking about where you parked your car or what you had for breakfast. Or there is the memory of how you swing a tennis racket to get a good backhand—motor memories.
__ All of those types of memories involve nervous systems being able to come up with a pattern of externally detectable behavior. The nervous system is able to read back material by a process called retrieval. Neuroscientists are interested in understanding both the process of storage and the process of retrieval. What enables you to remember a long-lost incident? What structural changes, what biochemical changes, what electro-physiological changes happen in the brain to store the memory, to allow it to be there for the many years you don’t access the memory?
__ And finally, what allows you to reach into that caldron of protoplasm and pull the memory out when you are asked at your school reunion, “Do you remember so-and-so?” and not only do you remember her, but you remember her vividly.
__ We are really at a primitive stage in [figuring out] how the brain works. It is very humbling as well as awe-inspiring to be studying an organ that weighs as little as it does and to understand as little about it as we do. The brain has the power to astound us in ways that the other organs really don’t anymore.
BW: It amazes me how little we actually do know about the brain.
RT: It is a problem of bridging together different levels of investigation. We know that it’s not one synapse or one vesicle that’s doing the job—but really thousands and millions of them. The challenge is to understand the organizing principles—the architecture that guides the use of the fragile and unreliable biological processes that make an overall outcome that is far more reliable than its component parts. Every single human behavior on a daily level involves a reliability that we come to expect of our fellow humans. All of this is being generated by synapses that fire on command with a reliability of only about 30 or 40 percent. Reliability relies then, on the ability to organize synapses in such a way so that their unreliable features are being washed out by the organization. And we do not completely understand that organizational feature.
BW: So how does it all work? Why is there reliability at all?
RT: Your experience is, of course, not at the level of what your individual synapses are doing. What we experience is the overall function of the system. Our main focus now is to move from what we know about those incredibly intricate but unreliable synapses and to get to the level where we can understand the calculation the brain is doing, to figure out the guiding principles that enable unreliable synapses to be made into reliable circuits.
BW: So what is the mechanism of memory storage?
RT: The general belief is that much of memory involves modification of the strength of synaptic connections. So if you are reading an article in Brain World, your brain processes that information, and in that processing synapses are being used and activated—and those synapses undergo a lasting change, which changes the properties of the circuits that the synapses are operating within. That change in the circuits’ properties is somehow read out [recalled] for the process of memory retrieval.
__ Imagine, in the brain, that sensation goes in, action comes out. Do that a few times, and then before we know it we are doing it more vigorously, more efficiently, and somehow that change in the strength of the synapse translates—through processes we do not necessarily understand—into a behaviorally measurable memory.
BW: What about not remembering something?
RT: If you make molecular manipulations that specifically make the synapse modifications go away, you can also abolish either the acquisition or the retrieval of the memory.
BW: Are there ways we can strengthen our memory on a daily, recognizable level?
RT: Neuroscientists generally subscribe to the theory, “use it or lose it.” We honestly believe that if you have an active life and use your brain you are more likely to continue to use your brain. Some people do crossword puzzles, learn new languages, memorize lists. It is not in my province to tell your readers what the best way to go about this is, but I think the most obvious thing I can say is that while the brain has incredibly sophisticated, specialized and non-generalized functions, it is also a collection of cells that, like heart cells, kidney or blood cells, need to be well taken care of. And the obvious ways of taking care of the brain are to get a lot of rest, get good nutrition, exercise it, and, most important of all, get a lot of sleep. There are a lot of things that we know happen during sleep which are specifically organized for the nervous system to replay certain patterns that it experienced, and to consolidate things that need to be remembered, and to also reset itself, so that things that are not to be remembered get dampened down. [bw]