GABA Cells in Schizophrenia and Bipolar Disorder: An Expert Interview With Dr. Francine M. Benes, MD, PhD

April 03, 2006

Editor's Note:
When proposed in the early 1970s, the suggestion of an "anatomy" of schizophrenia was met with skepticism. But the theory intrigued neuroscientist Francine M. Benes, MD, PhD, who set out to define the neural circuits that might be responsible for at least some forms of schizophrenia. Her journey in the decades since then is a fascinating story with significant implications for schizophrenia research and treatment. On behalf of Medscape, Jessica Gould interviewed Dr. Benes about her research into how disturbances in GABA and/or glutamate systems influence the development of schizophrenia and bipolar disorder. Dr. Benes is Director of the Program in Structural and Molecular Neuroscience at McLean Hospital in Belmont, Massachusetts, and Professor of Psychiatry (Neuroscience) at Harvard Medical School. She is also Director of the Harvard Brain Tissue Resource Center, or "Brain Bank," a National Institutes of Health-funded national resource that is the biggest distributor of postmortem tissue to investigators in the United States and around the world.

Medscape: I've read that the 'Aha!' moment that defined the direction of your career came during a lecture by Dr. Janice Stevens?

Dr. Francine M. Benes: At the time, I had just finished my PhD and I was a postdoctoral fellow in molecular neurochemistry at the City of Hope Medical Center in Duarte, California. I was attending the winter Brain Research Conference, which is held every year at a ski resort in Colorado. One evening, Janice Stevens, a neurologist who specializes in epilepsy, was giving a lecture on a paper she had just published in the Archives of General Psychiatry. It was entitled "An Anatomy of Schizophrenia?" In this article, Dr. Stevens discussed the similarities between schizophrenia and temporal lobe epilepsy and pointed out the significant overlap in symptoms. She suggested that schizophrenia might involve an abnormality in the temporal lobe, one that involves the dopamine system. At the time, it had been found that antipsychotic medications block dopamine receptors. Dr. Stevens is a pioneer, because she was the first investigator to suggest that a specific projection (the dopamine system) to an important region of the brain (the temporal lobe) might play a key role in distinctly human disease.

When I first heard her discuss her paper, I felt as if someone had hit me over the head. The idea that one might be able to understand schizophrenia, a uniquely human brain disorder that distinctively affects the way we think and perceive the world, in terms of a specific neural circuit or connection pattern was simply amazing.

At that time, psychiatric disorders had little or no place in the field of neuroscience. But a nascent interest was beginning to grow out of the dopamine hypothesis of schizophrenia. For a young scientist like myself, who had already worked as a neuroscientist on simple neural circuits in chickens and frogs, this had a powerful influence on my future path. By 1973, it was already clear that the study of more complex systems would help us to understand how the human brain enables us to think and feel.

I couldn't get the problem of schizophrenia out of my mind. The next day, I was going up the ski lift with a pathologist from Europe and told him how excited I was about Jan Stevens' talk. He smiled warmly and said, "There's nothing to that! People looked at the schizophrenia brain in the early part of the twentieth century and found nothing!" I thought, "How can there possibly be nothing there when so many people with schizophrenia are so sick?"

Something I should mention is that my very first research lab placement when I started graduate school was at Creedmoor Psychiatric Center in New York City. While there, I had the opportunity to see people with schizophrenia who were profoundly ill. That experience had a powerful influence on me.

When I had that conversation with the pathologist on the ski lift, I just had this feeling that this was something to look into. A couple of months later, I was literally walking down the street and I was thinking about how neural circuits may provide a substrate for higher cognitive functions such as logical thinking. At the time, I was teaching neuroanatomy with a distinguished scientist named Gordon Shepherd. He had just published The Synaptic Organization of the Brain. I was very impressed with his circuit diagrams for the cerebral cortex, particularly the influence that the so-called GABA cells might have on these circuits.

There is one other relevant piece to this story. A very famous psychiatrist named Thomas Detrie, who had been at Yale and later founded the Western Psychiatric Institute at the University of Pittsburgh, published a book entitled Modern Psychiatric Treatment. In one of the chapters, he provided a very provocative description of thought disorder in schizophrenia. I read this chapter with great interest and remember thinking, it may be possible to explain both normal and abnormal thinking on the basis of altered GABAergic integration with cortical circuits. A short time later, while walking down Cedar Street in front of Yale Medical School, I remembered the conversation with the neuropathologist at the winter Brain Research Conference a few months before. I suddenly stopped and thought, "I'm going to study neural circuitry in postmortem brains from patients with schizophrenia. That's what I have to do."

On the basis of those events, I made the decision to go to medical school so I could become a psychiatrist. In 1978, I graduated from Yale and became a resident at McLean Hospital, which, at the time, was the only research facility in the country with a brain bank that was collecting schizophrenia brains post mortem.

Medscape: At the brain bank, you work on "miswired circuits" in the brain. Can you tell me what that means?

Dr. Benes: Basically, when carrying out postmortem studies of schizophrenia and bipolar disorder, if you perform a standard neuropathological assessment, there are no obvious abnormalities that can be seen through a microscope using conventional staining techniques. Yet we know that patients with these disorders have significant disturbances in the way they respond to the environment and process information. Our work, which began in 1981, has focused on identifying the regions of the brain and types of neurons that might show abnormalities, using very specialized, highly sensitive quantitative techniques. The results of these studies have demonstrated that [the brains of people with these disorders] indeed [demonstrate] subtle abnormalities in the way neurons are connected to one another, or the way in which neurons talk to one another.

Medscape: How do you do this work?

Dr. Benes: Between 1981 and 2000, we used a combination of microscopic approaches to localize markers for various neurotransmitter systems. This, together with a careful process of hypothesis generation and testing, helped us to develop models of how neural circuits may be altered in schizophrenia. In the past 4 years, we have been using microarray-based gene expression profiling (GEP), a very broad screening tool that allows us to look at 20,000 genes simultaneously. We're combining this with laser-capture microdissection (LCM), which allows us to cut out very discrete portions of specific brain regions under the microscope. In so doing, we are able to disassemble a specific piece of circuitry into its component parts [and discern] many different subtypes of neurons, defined by their neurotransmitters, their synaptic connections, and their roles in integrating the activity of the circuit. Then we examine gene expression in these individual neuronal subtypes. Our goal is to identify what is called an endophenotype -- a profile of abnormal gene expression in specific neurons -- in schizophrenia brains. By performing the same studies in subjects with bipolar disorder, we are attempting to differentiate the endophenotypes for schizophrenia vs bipolar disorder. The goal of this work is to identify clusters of genes that impart the susceptibility for these disorders.

Medscape: How did you and your colleagues hone in on the GABA cell?

Dr. Benes: Our work during the past 15 years gradually pointed to a particular type of neuron, the GABA cell, as probably being abnormal in portions of the brain that are involved in motivation, attention, the processing of emotion at the conscious level, and the stressful response to emotional stimuli in the environment. These brain areas constitute what has been called the limbic lobe. Using the known connectivity of the regions comprising the limbic lobe, we were able to put together circuitry diagrams that expressed how the wiring patterns in these regions might be altered in schizophrenia. We still don't know, however, how those circuits may have become abnormal and what may sustain them in an abnormal state.

Microarray-based GEP has become a very important tool in neuroscience because it allows us to essentially go inside neurons and find out what's making them tick. Because it was possible to examine the expression of 20,000 genes simultaneously, it was an easy, strategic decision to use this form of technology to study the limbic lobe in relation to schizophrenia. No other form of technology could provide us with the same amount of information that the microarrays were able to provide. Initially, GEP only allowed us to study extracts of a whole region of the brain. Although we did see important changes in gene expression, we didn't know where in specific regions, such as the hippocampus, these changes might be found, and in what type of neurons these changes might be taking place.

When we coupled GEP with LCM, it allowed us to look individually at neuronal subtypes. So we're in the process of extending the model we had developed for the hippocampus to include multiple, functional clusters of genes that are involved in receiving synaptic stimulation and translating those synaptic signals into changes within the cell and changes in the overall modulation of the cell. So the changes we're looking at extend from the cell membrane through the cytoplasm to the nucleus, where all of the genetic material is contained, and back to the cytoplasm and various organelles such as mitochondria within the cytoplasm.

Medscape: What do you consider the most important discoveries you and your colleagues have made during the past several years?

Dr. Benes: I think the first important discovery is that the GABA system is abnormal in schizophrenia and bipolar disorder. The next most important discovery, one that we're actively working on right now, is how molecular mechanisms result in GABA cell dysfunction and how these mechanisms differ in schizophrenia and bipolar disorder. The basic pathophysiology of schizophrenia is different from the basic pathophysiology of bipolar disorder. Clinical observation teaches us that they really are different disorders. Not surprisingly, we're finding that the molecular mechanisms are fundamentally different in schizophrenia vs bipolar disorder. So now, for the first time, we're really beginning to appreciate how the endophenotype for the 2 disorders may be different. This is critically important because information of this type will begin to reveal which susceptibility genes are involved in each illness and this, in turn, will suggest novel forms of therapy that are unique to each disorder.

All of the drugs that we use now in psychiatry have been discovered by accident. We have no theoretical basis for any of our pharmacologic treatments, whether they be antipsychotics, antidepressants, mood stabilizers, or anxiolytics. It's incredible that our patients have done as well as they have. We believe, though, that our patients can do even better if the drugs we prescribe have a rationale based on an understanding of susceptibility and cellular endotypes. So the way we are discovering that involves looking across 20,000 genes and many different cell types in different regions of the brain. Strategies of this type will bring us to understand what's really wrong in the brains of patients with psychotic disorders. Our patients deserve to have rational therapies, and molecular neuroscience is going to satisfy that wish.

In addition, our finding that the GABA system is abnormal in both schizophrenia and bipolar disorder helps us to understand why there may be so much overlap between the clinical manifestations of the disorders. It may also help explain why antipsychotic drugs are used to treat both disorders.

Medscape: What do you think is up and coming in your field?

Dr. Benes: I think what is really coming down the line in an important way is stem cell research. It's going to reveal how neurons in the brain become differentiated, how they attain their functional competence during pre- and postnatal development, and how certain populations of neurons may become dysfunctional during late adolescence and early adulthood when schizophrenia typically begins. Stem cell research will lead us to new forms of therapy that can be applied early in the course of the illness and prevent its progression. We can only dream about such therapies right now, but they will become a reality in the future.

This interview is published in collaboration with NARSAD, The Mental Health Research Association, and is supported by an educational grant from Pfizer.


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