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Schizophrenia

Description
Schizophrenia is a serious brain disorder characterized by psychotic symptoms - thought disorder, hallucinations, delusions, paranoia - and impairment in job and social functioning. It is a disease that makes it difficult for a person to tell the difference between real and unreal experiences, to think logically, to have normal emotional responses to others, and to behave normally in social situations. Schizophrenia is a complex and puzzling illness. Even the experts in the field are not exactly sure what causes it. Some doctors think that the brain may not be able to process information correctly. Genetic factors appear to play a role, as people who have family members with schizophrenia may be more likely to get the disease themselves. Some researchers believe that events in a person"s environment may trigger schizophrenia.

Who is at Risk?
Risk factors for schizophrenia include biological, psychosocial, environmental, and sociocultural factors. Schizophrenia has a genetic component. People who have a close relative with schizophrenia are more likely to develop the disorder than are people who have no relatives with the illness. Many studies of people with schizophrenia have found abnormalities in brain structure and brain function. Schizophrenia is more common among people living in the city, those who live in the northern hemisphere, and those born during winter months. Early parental loss, either from death or separation, may increase the risk for schizophrenia. Schizophrenia is much more prevalent in lower socioeconomic classes, possibly as a result of increased stress and poor nutrition. The disease occurs twice as often in unmarried and divorced people as in married or widowed individuals.

Sources: A.D.A.M., Inc., Aurora Health Care, The HealthScout Network

Targeting Schizophrenia
Schizophrenia isn't curable in the true sense of the word, but it can be treated to a degree with anti-psychotic drugs. Through his research, TSRI Assistant Professor Ken Fish, Ph.D., is trying to better understand the molecular and cellular alterations that occur in the brains of schizophrenics so that more effective treatments can be developed. One of his research projects is focused on building mouse models that can mimic individual biologically induced behavioral deficits often associated, at least hypothetically, with schizophrenia. Two of these models lack the ability to produce either the very low density lipoprotein receptor (VLDR) or the apolipoprotein E receptor-2 (ApoER2), which are the receptors for the protein Reelin, a critical component for what is known as neuronal positioning during development. Without these receptors, the Reelin signal is not transmitted to migrating neurons, which results in the abnormal development of different brain regions, one of them the cerebral cortex.

The correct positioning of neurons in the layers of the cerebral cortex requires the Reelin signal, and is crucial for normal brain function. If the signal is disrupted, the cerebral cortical architecture is completely inverted. The oldest neurons do not pass the youngest, and end up closest to the top of the brain - the wrong spot for them. In many cases, these misplaced neurons are unable to perform their normal function. The mouse models are proving to be invaluable in Fish's efforts to understand the basic biology found in schizophrenia. It is the unknown quality of the disease that makes schizophrenia such a frightening and baffling condition, and helps explain the lack of treatment progress. As specific areas of the brain are better understood, the more accurately new, more efficient drugs can be created. Today, there are several antipsychotic therapies to treat schizophrenia. They remain hit or miss, treating some psychotic symptoms, but leaving others unchanged. The research on animal models should help make better drugs. Fish first hopes to validate his new mouse strains for their efficacy in the creation of new antipsychotic drugs, and then to involve both the pharmaceutical industry and other scientists to use his models to actually develop those drugs.

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Neurobiology of Reward, Motivation, and Emotion in Psychiatric Disorders
TSRI"s Athina Markou, Ph.D. and her colleagues have been focusing on the neurobiology of reward, motivation, and emotion in three psychiatric disorders: drug abuse, depression, and schizophrenia. Withdrawal from chronic administration of various drugs of abuse, including withdrawal from tobacco smoking results in a syndrome reminiscent of a major depressive episode and the negative symptoms of schizophrenia. Thus, the researchers working hypothesis is that the same neurological abnormalities mediate the depression seen during a major depressive episode, schizophrenia and drug dependence, and that the study of the neurobiology of drug-induced depression may lead to the discovery of novel therapeutic approaches for the treatment of depression and schizophrenia. In support of this premise, the researchers found that the depression-like aspects of drug withdrawal are reversed by clinically proven antidepressant treatments and partially by atypical antipsychotic drugs which are partially effective against the negative symptoms of schizophrenia. Current work in the laboratory focuses on investigating the role of glutamate and GABA neurotransmission in depression-like symptoms and in nicotine dependence in order to attempt to develop novel treatments for mental illness and tobacco smoking. Glutamate is the major excitatory neurotransmitter in the brain, while GABA is the major inhibitory neurotransmitter.

Recently, the researchers showed that blockade of a subtype of glutamate receptors (metabotropic glutamate receptor 2/3) reversed the depression-like aspects of nicotine withdrawal in rats, suggesting that blockade of these receptors may be a novel strategy to treat depression symptoms in depressed and schizophrenic patients. Other work indicated that blockade of another subtype of glutamate receptor (metabotropic glutamate 5) or of the GABA-B receptor subtype blocks the rewarding effects of nicotine. Nicotine is the main ingredient in tobacco smoking that leads to dependence and thus results in difficulty in quitting smoking. Thus, this data suggests novel pharmacological approaches to assist people in quitting smoking and treating the depression seen in many people after smoking has stopped. In conclusion, there appear to be neurobiological similarities in drug- and non-drug-induced depressions involving decreased glutamate transmission. Therefore, drugs that may positively modulate glutamate transmission may be effective antidepressants. Further, antagonists at specific glutamate and GABA receptors may assist people in quitting smoking and consequently avoiding the harmful health effects of tobacco smoking.

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Fat Molecules Make Bigger Brains
A team of TSRI scientists, led by Professor Jerold Chun, M.D., Ph.D., have described the effects of a particular phospholipids molecule on the development of mammalian brains. In their study, the scientists examined the effect of a phospholipid called lysophosphatidic acid (LPA) on developing brains in murine models. They found that LPA can act as a signal that induces neurogenesis - the formation of new neurons. Previously scientists believed that growth factors and other proteins largely controlled neural development and neurogenesis. Fat molecules have new roles that are only beginning to be understood. They potentially have profound effects on brain development. The work is significant because neural generation in early development predestines an organism for what happens later in life. The work may help clinicians and scientists understand some of the many diseases that arise from developmental defects that may be related to LPA signaling. Several childhood mental disorders and certain types of schizophrenia, for instance, are believed to be developmental in origin. The work may also help clinicians understand how to control stem cell differentiation - an important step for stem cell therapy.

Chun and his colleagues have been looking at what controls the formation of the cerebral cortex, the part of the brain that is believed to be involved in higher functions, like memory, cognition, and the interpretation of sensory input. The vast majority of these cerebral cortex neurons are generated before birth, and Chun and his colleagues wanted to know what signals controlled this process in early development. When developing brains are exposed to LPA, the brains spontaneously form the gyrated structures that are characteristic of higher mammals, like humans. These gyrations increase the surface area of the cerebral cortex that is believed to be essential to higher functions like intelligence and reasoning, which are characteristic of humans and other primates. Such gyrations are not normally seen in the brains of lower mammals, like mice.

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Behrens Research Opens Possibility of Therapeutical Intervention in Schizophrenia
TSRI Assistant Professor M. Margarita Behrens, Ph.D.'s research interests are centered in the hypoglutamatergic theory of schizophrenia and the role played by the parvalbumin-positive interneurons, specifically chandelier neurons, in the mechanisms of the disease. Her work centers on the study of NMDA-receptor subunit composition and NMDA-medicated intracellular signaling in these interneurons, as a way to predict the consequences of a hypofunction of these gluatamate receptors in this specific subtype of interneurons, which are key players in the control of cortical output. She was recently honored with a Young Investigator Award from the National Alliance for Research on Schizophrenia and Depression.

Behrens has found that GABAergic markers in parvalbumin-positive interneurons are especially sensitive to blockers of excitatory neurotransmission, where the interneurons lose their characteristic phenotype without cell loss. These results correlate with those found in schizophrenic subjects, where GABAergic markers in these interneurons are reduced, although the number of neurons is unaffected. This finding opens the possibility of therapeutical intervention aimed at increasing the GABAergic phenotype of these cells.

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Developing New Drugs for Schizophrenia
Noted neuroscientist Tamas Bartfai, Ph.D., is the director of the Harold L. Dorris Neurological Research Center at TSRI. In addition, he holds the Harold L. Dorris Chair in Neuroscience. Bartfai's work has implications for such diseases as depression, Alzheimer's disease, schizophrenia, and sleep disorders. Involved in the development of psychopharmaceutical agents for the last 20 years, he developed Zimelidine, the first selective serotonin reuptake inhibitor (SSRI) and two anti-psychotic agents used in the treatment of schizophrenia.

Recently, he elucidated the molecular mechanism of a new kind of antidepressant, substance P antagonist, which modifies a previously untapped neurochemical system. This finding may lead to the development of new and more effective drug targets against depression, as well as anxiety disorders and schizophrenia.

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Studying the Molecular Aspects of Schizophrenia for Better Diagnosis and Treatment
TSRI Professor J. Gregor Sutcliffe, Ph.D., and Professor Elizabeth Thomas, Ph.D., study the molecular aspects of schizophrenia so it can be better diagnosed and treated. Identifying which genes are making up the subtypes of the disorder would help find cures that would be specifically tailored toward schizophrenia. In a recent study, Sutcliffe and Thomas compared the expression levels of one protein in post-mortem tissue samples taken from various brain regions in schizophrenic and bipolar subjects to control subjects matched for age and other variables.

This was the third in a series of studies which addressed which genes are involved in these diseases. In one study, they looked at the effect of "chronic" dosing of the schizophrenia drug clozapine on gene expression in the brain. The brain responds to a large dose of the drug by increasing levels of expression of particular genes. Another study teased out some previously unknown differences between schizophrenia and bipolar disorder. For example, in the schizophrenic patients, the researchers found increases of the protein apoD expression in the amygdale, a small brain region associated with certain types of emotional behavior. In the bipolar patients, there was no such increase.

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A Protein That Affects The Shape Of Neurons
A century ago, much of the cutting-edge research in mental health was directed at understanding the psychological basis of psychiatric diseases: how memories and experiences play a role in our mental states. From this research emerged behavioral therapy, Freudian analysis, group therapy, and many other techniques that have been successfully applied to treatment in the field of mental health. Today, as we understand more and more about how the human body and the brain work on the cellular and molecular level, there is more interest than ever in the physiological basis for psychiatric diseases - the systems of interacting molecules and the chemical mechanisms through which these diseases manifest themselves. The reason for this interest is simple: there is an overwhelming need. According to the National Institute of Mental Health, over one fifth of all Americans -- more than 44 million individuals -- suffer from a diagnosable mental disorder in any given year. Now two scientists at The Scripps Research Institute are reporting a breakthrough in our understanding of the brain physiology that forms the basis for certain psychiatric diseases. In a recent issue of the journal Neuron, Associate Professor Shelley Halpain, Ph.D., and Research Associate Barbara Calabrese, Ph.D., describe how a protein called MARCKS affects the shape of neurons, particularly the part of the neurons known as dendritic spines, which are essential for learning and memory.

Because dendritic spines are so central to mental functioning, it's no surprise they are associated with neurological and psychiatric diseases. In mental retardation and autism, for instance, the shape of the dendritic spines are different. Under a microscope, the dendritic spines of many mentally retarded people are longer and appear more immature. In recent years, scientists have become increasingly aware of the possibility that a number of psychiatric and neurodegenerative diseases like Alzheimer's are also affected by synaptic changes brought about by spine morphology. The brains of schizophrenic patients or people suffering from mood disorders also show a reduced number of dendritic spines in the brain areas associated with these diseases. In the paper, the researchers show that MARCKS is a key player in the brain that affects the shape of these critical parts of human neurons. The research suggests a potential link between the molecular mechanisms involving MARCKS and the synaptic dysfunction observed in neurological diseases. MARCKS has a profound effect on already established, mature neurons. This type of altered neuronal morphology is one of the primary interests of Halpain and her laboratory. She and her colleagues have been developing and applying tools to study how synaptic connections are formed during the development of an organism, for instance, and to what extent they are altered or lost in certain diseases. The hope is that by understanding the biology of destabilization we can improve upon therapies that restore synapses.

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Scripps Florida Scientists Uncover Potential New Target for Schizophrenic Treatment

Scientists from Scripps Florida, part of The Scripps Research Institute, and colleagues have for the first time linked a specific microRNA to behavioral problems frequently associated with psychiatric disorders such as schizophrenia. The finding presents new opportunities in the development of potential treatments.

Scientists had previously known that a number of brain disorders—including schizophrenia, autism, attention deficit hyperactivity disorder (ADHD), mood disorders, and other psychiatric illnesses can involve a disruption in a signaling process in the brain involving N-methyl-D-aspartate (NMDA) glutamate receptors, which are regulators of rapid neurotransmission and synaptic plasticity—the ability of neuronal connections to change strength. Yet the specific molecular components of this disruption have remained a mystery. In the new study, however, the research team, led by Scripps Florida Professor Claes Wahlestedt, Ph.D., shed some light on the molecular mechanisms associated with NMDA-related behavior problems in mice. Specifically, the team discovered that disruption of NMDA signaling is associated with a reduction of a non-coding microRNA known as miR-219. Non-coding RNAs are small molecules that do not produce proteins, yet often play a vital role in gene expression.

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Scripps Research Study Shows How Microscopic Changes to Brain Cause Schizophrenic Behavior in Mice

Disrupting the function of a key molecule in the brain leads to microscopic brain abnormalities and schizophrenia-like behavior in mice. These abnormalities are similar to those seen in the autopsied brains of people who are diagnosed with schizophrenia in life, according to a team of scientists at The Scripps Research Institute. The scientists, led by Ulrich Mueller, Ph.D., a professor at Scripps Research, found several microscopic pathologies and behavioral traits that are hallmarks of schizophrenia, These findings in mice may help shed light on how schizophrenia, an often severe and debilitating disease, emerges in humans. In the study, Mueller, Research Associate Claudia Barros, and their colleagues also showed that the schizophrenic mice could recover normal behavior when treated with clozapine, a decades-old drug sometimes used to treat schizophrenia in people. This suggests that these mice might provide researchers with a good model system for studying schizophrenia and testing new drugs designed to treat people suffering from it.

Schizophrenia affects millions of Americans—about one percent of all people in the United States, according to the National Institute of Mental Health—and manifests in symptoms like hearing imaginary voices, paranoia, delusions of grandeur, severe apathy, and incoherent speech. Despite its prevalence, however, the causes of schizophrenia are not entirely understood. The scientific consensus is that the disease results from a combination of genes and other factors. Schizophrenia runs in families, which is strong evidence that inherited genes play a role, but the disease is not completely genetic. Some identical twins, for instance, are discordant—one will have the disease while the other will not. The fact that it can strike one genetically identical twin to the exclusion of the other means that there are more than just genes involved. Development may be another factor. People with schizophrenia usually do not begin showing signs of the disease until their late teens or early 20s. One of the current scientific hypotheses regarding schizophrenia, however, is that the disease is caused by developmental defects that occur in the brain long before the signs of the disease emerge. The mice that Mueller, Barros, and their colleagues studied would seem to lend credence to this hypothesis. In the new paper, the team describes what happens to the mice when they lose the function of a brain protein called neuregulin—an important developmental protein that helps the brain form its distinct structures early in development. Genetic studies have linked inherited forms of this protein and its receptors to schizophrenia and numerous other mental health problems.

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Scripps Research Scientists Shed Light On How Serotonin Works -- Findings Could Affect Development Of Future Depression, Schizophrenia Treatments
Scripps Research Institute scientists have shown for the first time that the neurotransmitter serotonin uses a specialized signaling pathway to mediate biological functions that are distinct from the signaling pathways used by hallucinogenic substances. The new findings could have a profound effect on the development of new therapies for a number of disorders, including schizophrenia and depression. Serotonin has tremendous influence over several brain functions, including the control of perception, cognition, sleep, appetite, pain, and mood and mediates these effects through interactions with receptors located throughout the central and peripheral nervous systems. The Scripps Research study shows that while both serotonin and hallucinogens act at the serotonin 2A receptor, serotonin utilizes a very specific pathway and its actions are independent of those produced by hallucinogens. Laura Bohn, Ph.D., an associate professor on the Florida campus of The Scripps Research Institute, led the study. Future drug discovery efforts to identify lead compounds for treatment of depression may consider focusing upon those that only engage that pathway. This work may also lend insight into the mechanisms that underlie the hallucinations that occur in schizophrenia.

This may be particularly important for the treatment of depression because traditional therapies, which focus on elevating serotonin levels, can sometimes produce serious side effects such as a serotonin syndrome. This syndrome is often accompanied by hallucinations, and is especially serious when antidepressant treatments such as selective serotonin reuptake inhibitors (SSRIs) are mixed with monoamine oxidase inhibitors (MAOIs). The scientists' current study supports a long-standing hypothesis that hallucinations may arise from the metabolites formed from elevated serotonin levels. Since there is a difference in the way the two neurotransmitters signal, this may represent a means to preserve the effects of serotonin while preventing the adverse side effects caused by the metabolites.

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