NARSAD's Fourteenth Annual Symposium
October 11 - 12, 2002

Session 3: Schizophrenia Research

Juan Burrone, Ph.D., of Harvard University , is studying the mechanisms that underlie the formation of the synapse, the part of the neuron which allows for communication with other neurons. Previous studies suggest that patients with schizophrenia have a decreased number of synapses. Dr. Burrone is examining a model system of synap-ses from the hippocampus in a culture dish. Using various manipulations, he has been able to elaborate some of the processes by which synapses develop in the growing brain. He demonstrated that if a neuron was silenced early in development, then very few synapses connect with that neuron and the electrical activity of those neurons is weaker. However, if a neuron is silenced late in development, there is no change in the number of synapses connecting to that neuron, but the electrical activity in these synapses is increased. In the "late silencing" scenario, it appears that the neurons have the ability to "recognize" that they are not receiving enough input from other neurons and ask for more input to compensate. This work may have important implications for our understanding of schizophrenia, which is theorized to result in part from abnormal development of synapses.

Comments by Dr. Carol Tamminga: "We've just had a chance to listen to a very bright, young neuroscientist at Harvard University who is doing very soph-isticated, cutting-edge research in order to answer questions on schizophrenia. This is a novel situation that wasn't happening ten years ago, but now that NARSAD is actually involved in funding young re-searchers, we can attract young people like this to answer questions in schizophrenia researchÉI am a clinician and I do research using human brain imaging. When I look at a PET scan, or I look at a regional cerebral blood flow scan, the area in the schizophrenic brain that misbehaves most often is the hippocampus. Dr. Burrone is looking at excitatory cells in rats that seem to be misbehaving in schizophrenia.

I say misbehaving because schizophrenia is not based on cell death, like Alzheimer's or Parkinson's disease. Schizophrenia is an illness in which people who have the illness continue to have all parts of their brain. There are some parts of their brain that just don't work right and if we knew how they weren't working right we could perhaps design specific treatments in order to help them work right. The level at which we believe that something is wrong with the brain in schizophrenia is at the level that Dr. Burrone was discussing. Based on the kind of work that he is doing, we will be able to find out what the neurochemical basis for the hippocampal changes in the brain are and we can then use rational and novel approaches to find medicines to treat the illnesses. Once Dr. Burrone gets his model all set up, he can test it to see what the effect of the medications we now use are on the hippocampal activity. This really give us a whole other window into understanding what our current medications are."

Dane Chetkovich, M.D., Ph.D., of Northwestern University , is studying the mechanisms by which glutamate receptors are moved from where they are made, deep within a brain cell, to the synapse, the gap between nerve cells where communication takes place. The glutamate receptor may have particular relevance to schizophrenia, because drugs that block glutamate receptors are known to cause a psychosis that resembles this disorder. Dr. Chetkovich is using a mouse, called stargazer, which has a mutated gene for a protein that makes the glutamate receptor move to the synapse. It has been demonstrated that the last three molecules of the stargazer protein are the most important for this process to occur. This process can be modulated by a group of enzymes called protein kinases. This work should ultimately lead to a better understanding of how the glutamate receptor system functions, with potential implications for medication development in schizophrenia.

Dr. Tamminga: "You all remember some time ago when all we heard about was dopamine and the role of dopamine, a neurotransmitter, in schizophrenia. The field of neuroscience has grown so fast and so broadly that not only do we know a lot about other transmitters, like the one that Dr. Chetkovich talked about today, glutamate, but we can even understand the interactions between these transmitters, between norepinephrine, serotonin and dopamine in the glutamate system. Dr. Chetkovich is studying the stargazer rat and he is finding out very, very interesting things about substances in the brain of this animal that make it behave in an abnormal way. Now we can actually look for these substances, given that he puts together a hypothesis of schizophrenia and suggests a region of the brain to look at. These are studies we can actually directly translate to schizophrenia using human post-mortem tissue, using some human in vivo imaging techniques. There are ways that we can take very sophisticated and specific research, like that of Dr. Chetkovich, and translate it to the human situation.

Kenneth Fish, M.D., of the Scripps Research Institute , is studying two related proteins that play important roles in brain development. The first protein is called reelin, which is produced by embryonic brain cells and helps guide their migration. Patients with schizophrenia have a marked reduction in brain reelin, suggesting that this molecule may be involved in the cause of the disorder. The second protein being studied is called mDab1, which helps to transmit the signal that reelin generates. Using young neurons from the hippocampus, Dr. Fish has shown that this occurs when the reelin protein stimulates the addition of a phosphate group to mDab1. The elaboration of interactions between these two proteins may lead to new insights into how reelin affects the way in which newly formed neurons migrate from the inner to the outer regions of the brain during prenatal life. This may help to provide a biochemical basis to the neurodevelopmental theory of schizophrenia, which posits that the disorder results from a defect in brain development.

Dr. Tamminga: "Let me just put some of what Dr. Fish has talked about into some sort of context about schizophrenia. One of the big risk factors for schizophrenia is second trimester viruses, second trimester famine, second trimester accidents that happen in intra-uterine development. The human cortex develops during the second trimester of pregnancy, 12 to 24 weeks. We already know that in schizophrenia the kind of cortical development that Dr. Fish is talking about is vulnerable to influences that actually produce the illness. This reelin protein that Dr. Fish is working with has been identified as abnormal in schizophrenia and so he is setting up a system to functionally study the protein that we know as abnormal in the illness. One of the nice things, I could add, about what neuroscience is telling us these days - new ways to look at the illness. The kinds of tools we have available today may actually redefine the identity and the definition of the illness."

Anna Francesconi, M.D., of Albert Einstein College of Medicine , is studying a class of brain receptors called metabotropic glutamate re-ceptors (mGluRs). Previous studies have shown that drugs which activate mGluRs alleviate some of the "symptoms" of schizophrenia in animal models. Metabotropic glutamate receptors regulate the release of glutamate from neurons and modulate the transmission of glutamate. Dr. Francesconi aims to identify the cellular components involved in these ef-fects. In a first step, different targeting signals carried by two versions of mGluRs have been identified. Ge-netic and biochemical techniques are being utilized to determine which proteins interact with these targeting signals. This work has the potential to provide new information on the function of mGluR, which may ultimately lead to new medications that target this receptor system in schizophrenia.

Dr. Tamminga: "The glutamate system is probably much more complicated in the brain than the dopamine system. Ever since we understood that drugs that block the dopamine system help schizophrenia, we've looked for something wrong with the dopamine system. We found little bits of things every now and again, but the question of why the drugs that block the dopamine system are helpful in schizophrenia hasn't been fully answered yet. When we use brain imaging studies in people with schizophrenia, we can actually see which areas are abnormal. We can use the drugs that Dr. Francesconi is talking about to try to normalize or affect those regions of the brain."

Adrian Preda, M.D., of Yale University , is using a new method, called diffusion tensor imaging (DTI), which provides detailed visualization of nerve fibers in the brains of living subjects. Previous studies suggest that abnormalities in the connectivity between nerve cells may be present in schizophrenia, which could explain some of the symptoms of this disorder. Dr. Preda has used this method in a group of patients with schizophrenia, patients with other severe mental illnesses, and a control group. Preliminary results suggest that patients with schizophrenia have an abnormal pattern of fiber tracking.

Further work will examine whether whole fibers or only parts of nerve fibers are affected, and the brain regions in which these abnormalities are found. This work may result in a better understanding of the specific disruptions of neural connectivity that are found in schizophrenia.

Dr. Tamminga: "What Dr. Preda is studying is very important. When all of us are about to perform a task, the brain doesn't just do that task all in one place. There are specialized areas of the brain, perhaps on the left in the front and the right in the back which are specialized to perform these kinds of mental functions. And every task, if you will, takes a combination of these regions in order to perform the task. Dr. Preda has just told us that the way these regions communicate with each other is through fiber pathways within the brain, and through these white matter tracks, and that these fiber pathways going from one area to the other seem not to be working; seem not be carrying the information, in people with schizophrenia. So that when people with schizophrenia do certain cognitive tasks they seem to have only part of their brains available to them in order for them to perform the task. Dr. Preda's experiments allow us to directly look at these pathways."

• Session 1: Basic Science Research

• Session 2: Affective Disorders Research

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