Toward a New Approach to Depression
An Interview with Paul Greengard, Ph.D.

by Brenda Patoine

April, 2007

Q: Your laboratory recently discovered a protein, dubbed P11, that you believe may be a key to understanding and treating depression better. What is the significance of the P11 finding?

A: P11 is important because it controls the localization of a very important class of serotonin receptors (the 5-HTIB receptors). Within nerve cells, P11 recruits the 5-HT1B receptors from the interior of the cells, where they are not functional, to the membrane on the cell surface, where they become functional and interact with serotonin molecules released by other cells. P11 is required for this movement.

To put this in context, there are currently three general classes of antidepressant drugs: SSRIs, tricyclics, and MAO inhibitors. All three cause an increase in serotonergic signaling, though they do it in different ways: the SSRIs block serotonin reuptake; the tricyclics block serotonin and norepinephrine reuptake; and the MAO inhibitors block serotonin and norepinephrine breakdown. The common short-term effect of all three classes of drugs is to raise the level of serotonin in the presence of a fixed number of serotonin receptors.

What P11 does is increase the level of receptors in the presence of a fixed amount of serotonin. Theoretically, increasing the level of serotonin receptors should produce an antidepressant effect because there would be more receptors to detect the serotonin. In fact, we found that if we knocked out P11 in mice, the animals behaved in a depressed manner, and if we over-expressed P11, the animals behaved as if they had been given an antidepressant.

We also found that, with extended use, antidepressants raise the level of P11 in the brains of experimental animals. And both in animal models of depression and in human post-mortem brain tissue, we found that depressed subjects had lower levels of P11 than non-depressed controls. To the best of my knowledge, this is the first example where there is a very good correlation between the level of a protein and state of depression, suggesting that P11 may be a key determinant in whether or not we are depressed. So this is a rather exciting starting point for trying to understand the biology of P11 and its relation to depression.

Q: Where are you now with research on P11?

A: Based on our work to date, we can make several conclusions. We know that antidepressants raise the level of P11; that P11 recruits serotonin receptors to the cell membrane; and that depressed animals and people have lower levels of P11 than normals. We also know that if you lower P11 levels, animals get depressed, and if you raise P11, the depression is relieved. One of the projects we’re working on now is to try to understand the mechanisms by which antidepressants raise the level of P11. It’s possible that this may be the key to how antidepressants are working, a theory that is not incompatible with other theories of how antidepressants exert their effects, such as the recognized effect these drugs have on neurogenesis.

We also want to understand how P11 recruits serotonin receptors to the membrane, and how this increase in serotonin receptors at the membrane leads to the observed antidepressant behavior. These are the more urgent questions we’re trying to address.

Beyond these central questions, we want to know if P11 levels in the blood can be used as a biomarker for depression. We’re also looking at other members of the large family of so-called S100 proteins, to which P11 belongs. Since there are many different types of serotonin receptors, we’re now asking which of the S100 proteins interact with which serotonin receptors, to see if these phenomena we’ve observed could have broader significance. We don’t know the answers yet; we’re just setting up the methodology to do these studies now.

Q: Does this suggest that P11 might be used as a new form of antidepressant?

A: Because P11 is a protein, it couldn’t be taken orally—it wouldn’t be in the form of a pill like Prozac. Conceivably, P11 could be harnessed to treat depression using gene therapy approaches aimed at raising its level of expression. We’re doing some studies in collaboration with Michael Kaplitt at Cornell to see whether we can use RNA interference technology to knock down or raise the level of P11 in specific brain regions suspected to be important in depression, and then see what happens behaviorally in experimental animals. Theoretically, this work could prove useful. The more traditional approach (which we are also doing) is to identify the mechanisms by which current antidepressant drugs raise the level of P11 and develop drugs that do that more effectively.

Q: Why do we need another antidepressant?

A: About one-third of patients who are severely depressed don’t respond to any antidepressant. Among the two-thirds who do respond, many often suffer from side effects, which are sometimes severe. Current antidepressants take two to three weeks or more to have an effect, which is a very worrisome situation in severely depressed people because there may be a suicide risk. P11 would be a totally new approach, one that conceivably could provide benefits to a population of patients who either don’t respond to antidepressants now on the market or who could respond with fewer side effects.

Q: You were awarded the Nobel Prize in Physiology or Medicine in 2000 for your work on post-synaptic pathways in the dopamine system, and last year you turned 81. What drives you in your research these days?

A: What continues to drive me is my excitement about understanding the brain, which is greater than ever; I feel there’s so much more that’s exciting now. It’s a very stimulating environment because there are so many excellent people, including talented younger people, coming into the field, and there’s so much more information coming out all the time. It would be impossible not to be excited about all the progress we’ve made in neuroscience.

Q: What would you like to see occur in your lifetime in brain science?

A: It would be nice to understand the locus of depression in the brain. What are the abnormalities in the neural circuitry that lead to depression? There is some progress being made in this area. In Alzheimer’s disease, it would be nice to know the difference between vulnerable and non-vulnerable neurons. For all of the diseases involving the dopamine system, it would be very nice to understand why dopaminergic neurons in the substantia nigra degenerate to a much greater extent than those in the ventral tegmental area, and what the adaptations are in the cells in the striatum that are the target of those dopaminergic neurons.

It would also be interesting to learn more about the causes of schizophrenia; we really know so very little. There’s good evidence that it is a developmental disorder, but the actual cause is still unclear. The genetic studies have provided some exciting leads, but not very many. How is the dopamine and glutamate signaling circuitry involved in producing the schizophrenic state? A lot of these problems are approachable now, whereas they weren’t 10 years ago.

Q: What surprises you most about science today?

A. One thing that surprises me is the progress that has taken place in the computer revolution, particularly the increased speed of calculation and the ubiquitous application of new methods of calculation. These things are advancing far faster than those of us not in that field expected. Right now, computational models are being used to digest the vast amounts of data being generated by modern molecular biological techniques. That has had a profound impact on research, especially in genomic and genetic studies.

I think these tools will become increasingly important to understanding the brain. As we learn more about all the genes that are expressed in all the different types of cells in the brain, and about the myriad connections that any given nerve cell has with others in the brain directly or indirectly, there is going to be an increasing role for computer modeling.

Q: Did you ever imagine you’d be able to do these sorts of things when you started out in neuroscience?

A: The field has advanced much faster than I could have imagined. That’s largely due to the revolution in molecular biology and the development of a lot of very powerful tools. For example it is now possible to change the level of a given gene in any given cell type at any stage of development. You can now remove or over-express all sorts of genes to study their effects on biochemical, physiological and behavioral properties of animals modified in that way. It is now possible to change the level of a protein in a single cell type at a certain time, to create inducible, conditional knockouts. We have new electrophysiological techniques that enable one to record from single cells, including from genetically modified cells or cells from genetically modified whole animals. There are also advances in imaging that make it possible to visualize, in real time, how cells change in live animals under various experimental conditions.

These advances have all greatly informed research, and make it possible to test hypotheses in ways that were never feasible before. Because all of these techniques are available, there is also more and more collaboration among laboratories. So I’m extremely optimistic about the future of the field.

Q: How important is it that scientists “sell” science to the public?

A: I think the more that scientists can communicate the excitement of our field to the lay public, the more support the lay public will want to see the scientists given by the government. We’re moving closer and closer to major advances in many different areas of medicine, and I have the sense that this is also true for every field of science. The more we can communicate this work to the lay public, the more likely they will be to urge their Congressional representatives to support these areas of research.