Category: Schizophrenia

The strongest known recurrent genetic cause of schizophrenia impairs communications between the brain's decision-making and memory hubs, resulting in working memory deficits, according to a study in mice.

"For the first time, we have a powerful animal model that shows us how genetics affects brain circuitry, at the level of single neurons, to produce a learning and memory deficit linked to schizophrenia," explained Thomas R. Insel, M.D., director of the National Institute of Mental Health (NIMH), part of the National Institutes of Health. "This new research tool holds promise for ultimately unraveling the underlying anatomical connections and specific genes involved."

NIMH grantees Joshua Gordon, M.D., Ph.D., Joseph Gogos, M.D., Ph.D., Maria Karayiorgou, M.D., and Columbia University colleagues, report on their discovery in genetically engineered mice in the April 1, 2010 issue of the journal Nature.

"Our findings pinpoint a specific circuit and mechanism by which a mutation produces a core feature of the disorder," said Gordon, who led the research.

Researchers have suspected such a brain connectivity disturbance in schizophrenia for more than a century, and the NIH has launched a new initiative on the brain's functional circuitry, or connectome. Although the disorder is thought to be 70 percent heritable, its genetics are dauntingly complex, except in certain rare cases, such as those traced to the mutation in question.

Prior to this study, neuroimaging studies in schizophrenia patients had found abnormal connections between the brain's prefrontal cortex, the executive hub, and the hippocampus, the memory hub, linked to impaired working memory. It was also known that a mutation in the suspect site on chromosome 22, called 22q11.2, boosts schizophrenia risk 30-fold and also causes other abnormalities). Although accounting for only a small portion of cases, this tiny missing section of genetic material, called a microdeletion, has repeatedly turned up in genetic studies of schizophrenia and is an indisputable risk factor for the illness.

Still, the mutation's link to the disturbed connectivity and working memory deficit eluded detection until now.

To explore the mutation's effects on brain circuitry, Gogos, Karayiorgou and colleagues engineered a line of mice expressing the same missing segment of genetic material as the patients. Strikingly, like their human counterparts with schizophrenia, these animals turned out to have difficulty with working memory tasks — holding information in mind from moment to moment.

Successful performance of such tasks depends on good connections in a circuit linking the prefrontal cortex and the hippocampus. To measure such functional connections, Gordon and colleagues monitored signals emitted by single neurons implanted in the two distant brain structures while mice performed a working memory task in a T-maze (see below).

The more in-sync the neurons from the two areas fired, the better the functional connections between the two structures — and the better the mice performed the task. Moreover, the better the synchrony to start with, the quicker the animals learned the task. The more synchrony improved, the better they performed.

As suspected, the mice with the chromosome 22 mutation faltered on all counts — showing much worse synchrony, learning and performance levels than control mice.

"Our results extend beyond those in patients by showing how an undeniable genetic risk factor for schizophrenia can disrupt connectivity at the level of single neurons," explained Gordon.

The researchers plan to follow up with studies into how the mutation affects brain anatomical and molecular connections and the workings of affected genes.

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Journal Reference:

1. Torfi Sigurdsson, Kimberly L. Stark, Maria Karayiorgou, Joseph A. Gogos, Joshua A. Gordon. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature, 2010; 464 (7289): 763 DOI: 10.1038/nature08855

— In what may provide the most compelling evidence to date, researchers at Columbia University Medical Center have illuminated how a genetic variant may lead to schizophrenia by causing a disruption in communication between the hippocampus and prefrontal cortex regions of the brain, areas believed to be responsible for carrying out working memory. Findings are published in the current online edition of Nature.

This discovery coincides with the 15th anniversary of the first identification of the link between schizophrenia and a genetic mutation — a microdeletion on human chromosome 22 — known as 22q11 deletion, by Columbia Psychiatry researcher Maria Karayiorgou, M.D., a coauthor on the research. Previous studies have shown that approximately 30 percent of patients with this deletion will go on to develop schizophrenia.

"We know that this genetic deficit predisposes us to schizophrenia, and now we have identified a clear pathophysiological mechanism of how this deletion confers this risk for schizophrenia," said Dr. Karayiorgou. Dr. Karayiorgou discovered the link between the 22q11 mutation and schizophrenia in 1995. Since then, Dr. Karayiorgou and Joseph A. Gogos, M.D., Ph.D, a senior author on the research, have established and pursued research focusing on the neurobiology of this mutation.

Though schizophrenia is best known for its delusions and hallucinations, it is the disease's impact on such cognitive abilities like working memory — a key element of executive functioning — that best predict how well a person will function in society.

Using a mouse model with the 22q11 deletion, senior authors Joshua Gordon, M.D., Ph.D., and Joseph A. Gogos, M.D., Ph.D., and their teams, recorded the neural activity of the mice while they performed a cognitive task of working memory, and found that their performance was either completely disrupted, or was impaired, compared to that of the healthy mice.

(Dr. Karayiorgou is professor of psychiatry, Dr. Gogos is associate professor of physiology and neuroscience, and Dr. Gordon is assistant professor of psychiatry at Columbia University Medical Center).

In healthy mice, the hippocampus sends spatial information to the prefrontal cortex, but in the mouse model of the 22q11 mutation there is a breakdown in the connection and this communication is either weakened or fails completely.

As part of the cognitive trial, the mice were tested as they navigated a t-shaped maze. In order to successfully complete the task, the mice had to recall the direction in which they traveled, and then choose to go in the opposite direction to receive their next reward. While the healthy mice easily learned the task, mice carrying the schizophrenia mutation took longer to master it, demonstrating a behavioral deficit of the task in the mouse model of schizophrenia.

"We found that successful completion of the task in our healthy mice required the two regions of the brain — the hippocampus and the prefrontal cortex — to work together, and in our mouse model, the information transfer was less efficient, or was unable to take place at all," said Dr. Gordon.

In addition, the researchers reported that they were able to show the extent of the deficit in individual mice.

"There was a variation in how much of a deficit they showed, and that correlated with the degree of the behavioral deficit, so that for individual mice that have less communication between these structures, there was more of a behavioral deficit," said Torfi Sigurdsson, Ph.D., a postdoctoral research scientist in Dr. Gordon's laboratory at Columbia Psychiatry and a coauthor on the paper.

Recent human imaging studies have suggested the possibility that there may be abnormalities in the functional connectivity between the hippocampus and prefrontal cortex in schizophrenia, however, it remained unclear how such findings related to a cause of the disease, like that of a genetic risk variant, or if they were the result of the disease itself or medications used.

"Here we are really at the level of the individual cells, so our findings extend beyond patient studies by showing how disrupted connectivity can arise at the level of single neurons, as a result of a genetic risk variant," said Dr. Sigurdsson.

Another strength of the study, according to the researchers, is that the communication can be measured directly between the two regions.

"It unequivocally establishes a deficit in that communication in a way that the early studies could not — not only because we can isolate the genetics of the disease, but we can also measure the connectivity between these structures directly," said Dr. Gordon.

"The 22q11 deletion mouse model allows us to explore how these mutations alter brain function and the abnormal behavior that we see in schizophrenia patients. This is exactly what our study and our research program on 22q11, in general, has accomplished," said Dr. Gogos.

"We now know that one of the consequences of that deletion is to disrupt functional communication between these two brain regions, and we have evidence from the study that the disruption actually has an impact on a cognitive behavior that is disrupted in patients, so it gives us a really strong indication of how the deletion can contribute to the development of schizophrenia," he added. "It is possible that similar abnormalities in functional connectivity may also account for other symptoms of the disease, and can be used to better assess treatment response, and, most importantly, to develop new medications."

Next, the researchers plan to test the structural links between the hippocampus and prefrontal cortex, since it appears likely that synchrony between these two regions is mediated through anatomical connections. The researchers will examine how the anatomical and synaptic properties of these connections change in this mouse model and will aim to identify the genes that account for this change.

Authors of the Nature study are Torfi Sigurdsson, Kimberly L. Stark, Maria Karayiorgou, Joseph A. Gogos and Joshua A. Gordon.

This study was supported in part by the Simons Foundation, the National Institute of Mental Health (NIMH), and the Lieber Center of Schizophrenia Research and Treatment.

Contrary to popular belief, schizophrenia is not a split personality; it is a chronic, severe, and disabling brain disorder that affects just over one percent of the adult population and is characterized by loss of contact with reality (psychosis), hallucinations (usually, hearing voices), firmly held false beliefs (delusions), abnormal thinking, a restricted range of emotions (flattened affect) or inappropriate and disorganized behavior, social withdrawal, and diminished motivation.

The disease often strikes in the early adult years, and although many individuals experience some recovery, many others experience substantial and lifelong disability. People with schizophrenia often have problems functioning in society and in relationships and are over-represented on disability rolls and among the homeless and imprisoned.

What precisely causes schizophrenia is not known, but current research suggests a combination of hereditary and environmental factors. Fundamentally, however, it is a biologic problem (involving changes in the brain), not one caused by poor parenting or a mentally unhealthy environment.

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Journal Reference:

1. Sigurdsson et al. Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature, 2010; 464 (7289): 763 DOI: 10.1038/nature08855

 An estrogenic drug that influences neurotransmitter and neuronal systems inthe brain is showing promise as an effective therapy for women who suffer from schizophrenia.

A study has found that Raloxifene — a synthetic estrogen currently used to treat osteoporosis — has beneficial effects on postmenopausal women with schizophrenia, with a test group experiencing a more rapid recovery from psychotic and other symptoms compared to control groups.

Research project leader and Director of the Monash Alfred Psychiatry Research Centre (MAPrc) Professor Jayashri Kulkarni said women in the trial who were given 120mg a day of the unique selective estrogen receptor modulator had a significantly greater improvement in psychosis symptoms compared with those on placebos and lower doses.

"The results were very promising. Under daily treatment with this 'brain estrogen', the women in the study had improvement in their key psychosis symptoms and also experienced enhanced memory and higher learning capacity," Professor Kulkarni said.

"Many patients in this study had longstanding, persistent schizophrenia, so we are delighted that they experienced improvements in their mental well-being. We will continue to investigate the efficacy of Raloxifene which is a currently available treatment for osteoporosis in postmenopausal women."

"Unlike estradiol, the standard estrogen found in the oral contraceptive pill or hormone replacement treatment, this type of estrogen did not have the side effects on breast, uterus and ovarian tissue that we worry about with other forms," Professor Kulkarni said.

While the findings were still tentative given the relatively small sample size, the research team is cautiously optimistic that ongoing trials will further confirm the positive therapeutic potential of the drug for postmenopausal women, and potentially for other cohorts.

Professor Kulkarni said the findings, published in Psychoneuroendocrinology, would offer hope to the hundreds of thousands of women in Australia who suffer from schizophrenia.

"Our results indicate that this therapy really could revolutionise treatment options for women with schizophrenia. While at this stage we are just investigating its use in postmenopausal women, we are planning further research using hormone treatments in younger women and men suffering from psychotic illnesses," Professor Kulkarni said.

"One in five of us will experience a mental illness at some point in our lives. These conditions have a huge impact not only the sufferer, but on their families and Australian communities, so it is critical that governments and the private sector invest in research to develop effective treatment options."

Professor Kulkarni pioneered research into hormonal factors and treatments in psychosis after assessing epidemiological studies that indicated gender differences in the age and onset of schizophrenia, and from clinical observations that symptoms were more severe in women during premenstrual, perimenopausal and postnatal phases. The current study follows on from previous trials of estrogen and anti-estrogen treatment for women and men with a variety of mental illnesses.

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Journal Reference:

1. Jayashri Kulkarni, Caroline Gurvich, Stuart J. Lee, Heather Gilbert, Emmy Gavrilidis, Anthony de Castella, Michael Berk, Seetal Dodd, Paul B. Fitzgerald, Susan R. Davis. Piloting the effective therapeutic dose of adjunctive selective estrogen receptor modulator treatment in postmenopausal women with schizophrenia. Psychoneuroendocrinology, 2010; DOI: 10.1016/j.psyneuen.2010.01.014

 Rhesus monkey babies born to mothers who had the flu while pregnant had smaller brains and showed other brain changes similar to those observed in human patients with schizophrenia, a study at the University of Wisconsin-Madison in collaboration with the University of North Carolina at Chapel Hill has found.

The study, published online by the journal Biological Psychiatry, is the first study done with monkeys that examines the effects of flu during pregnancy. Results from this study support findings from rodent studies suggesting this type of infection may increase the risk of schizophrenia in the offspring, said lead author Sarah J. Short, Ph.D.

Short worked on the study while earning her doctorate at Wisconsin and now is a post-doctoral fellow at UNC working with John H. Gilmore, M.D., professor of psychiatry in the UNC School of Medicine.

"This was a relatively mild flu infection, but it had a significant effect on the brains of the babies," Short said. "While these results aren't directly applicable to humans, I do think they reinforce the idea, as recommended by the Centers for Disease Control and Prevention, that pregnant women should get flu shots, before they get sick."

In the study, 12 rhesus macaques were infected with a mild influenza A virus 1 month before their baby's due date, early in the third trimester of pregnancy. For comparison, the study also included 7 pregnant monkeys who did not have the flu.

When the babies were 1 year old, magnetic resonance imaging (MRI) scans were taken of their brains. Researchers also assessed the babies' behavioral development at that time.

The babies born to flu-infected mothers showed no evidence of direct viral exposure. Their birth weight, gestation length and neuromotor, behavioral and endocrine responses were all normal.

However, the MRI scans revealed significant reductions in overall brain size in the flu-exposed babies. In addition, the scans found significant reductions of "gray matter" (the portion of brain tissue that is dark in color) especially in areas of the brain called the cingulate and parietal lobe, and significant reductions of "white matter" (brain tissue that is lighter in color) in the parietal lobe.

The cingulate is located in the middle of the brain, but spans a broad distance from front to back and relays information from both halves of the brain. This structure is important for numerous cognitive function related to emotions, learning, memory, and executive control of these processes to aid in decision-making and anticipation of rewards. In addition this structure also plays a role in regulating autonomic processes, such as blood pressure and respiratory control. The parietal lobe comprises a large section on both sides of the brain between the frontal lobes and the occipital lobes, in the back of the brain. This part of the brain integrates information from all the senses and is especially important for combining visual and spatial information.

"The brain changes that we found in the monkey babies are similar to what we typically see in MRI scans of humans with schizophrenia," said Gilmore. "This suggests that human babies whose mothers had the flu while pregnant may have a greater risk of developing schizophrenia later in life than babies whose mothers did not have the flu. Normally that risk affects about 1 of every 100 births. Studies in humans suggest that for flu-exposed babies, the risk is 2 or 3 per 100 births."

Most of the work of the study was done at the Harlow Center for Biological Psychology, which is part of Wisconsin's Department of Psychology. The center's director, Christopher Coe, Ph.D., is senior author of the study. Gilmore, a schizophrenia researcher who has led several studies that used MRI scans of newborn human brains, led the analysis of MRI data in the pregnancy and influenza study.

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Journal Reference:

1. Sarah J. Short, Gabriele R. Lubach, Alexander I. Karasin, Christopher W. Olsen, Martin Styner, Rebecca C. Knickmeyer, John H. Gilmore, Christopher L. Coe. Maternal Influenza Infection During Pregnancy Impacts Postnatal Brain Development in the Rhesus Monkey. Biological Psychiatry, 2010; DOI: 10.1016/j.biopsych.2009.11.026

— In one of the first such studies involving human patients with schizophrenia, researchers at UC Davis have provided evidence that deficits in a brain chemical may be responsible for some of the debilitating cognitive deficits — poor attention, memory and problem-solving abilities — that accompany the delusions and hallucinations that are the hallmarks of the disorder.

The study, published online March 10 in the Journal of Neuroscience, suggests an important avenue of inquiry for improving cognitive function in the more than 2 million Americans who suffer from schizophrenia, according to Jong H. Yoon, an assistant professor of psychiatry and behavioral sciences at UC Davis Health System and the study's lead author.

"We still know very little about the neurobiology of schizophrenia, particularly at the level of specific circuits and molecules and how their impairments affect behavior and cognition in the disease," said Yoon, a researcher at the UC Davis Imaging Research Center. "We need this level of specificity to guide targeted treatment development. This is one of the first studies to show that there is a strong association between cognitive deficits and a decrease in a particular neurotransmitter."

Schizophrenia is characterized by psychosis — abnormalities in the perception or expression of reality. Sufferers may experience visual or auditory hallucinations and have paranoia, delusions and disorganized speech and thinking. But they also experience profound cognitive difficulties that interfere with daily functioning.

Psychosis is treated with a variety of antipsychotic medications that dampen overactivity of the neurotransmitter dopamine, an acknowledged cause of psychotic behavior. But no medications are available to address cognitive deficits in schizophrenia because the source of the deficits has not been determined. Deficits in one brain chemical, the neurotransmitter gamma-aminobutyric acid, or GABA, have been implicated as playing a causal role in cognitive difficulties in people with schizophrenia in research involving animal models and post-mortem analyses of GABA concentrations in human schizophrenic brains.

"People think of schizophrenia as being related to psychosis. But patients' cognitive limitations can be even more debilitating for them," said Cameron Carter, professor of psychiatry and behavioral sciences, director of the Imaging Research Center and the study's senior author. "This study actually looked at brain chemistry in live patients in relation to cognitive performance to determine the underlying neurobiology of the cognitive deficits. Our ultimate goal is discovering ways to help patients lead more productive lives."

Yoon and his colleagues measured the levels of GABA in the visual cortexes of the brains of 13 study subjects with schizophrenia and 13 control subjects without the disorder. The measurements were conducted with high-field magnetic resonance spectroscopy, a technique that involves using a magnetic resonance imaging scanner to examine neurotransmitter activity. The schizophrenic patients were found to have a deficit in GABA of about 10 percent when compared with their non-schizophrenic counterparts.

The second half of the study involved demonstrating the significance of the neurochemical deficit on cognition and behavior. To do this the researchers measured the visual perception of the subjects for whom GABA levels were assessed by showing them a well-known illusion in which the presence of a high-contrast surrounding region inhibits the ability to perceive information in the center of the visual field.

The researchers showed that this surround-suppression illusion had less of an effect on patients with schizophrenia, resulting in a highly unusual situation in which they outperformed healthy subjects when baseline differences in generalized task performance were accounted for. The researchers then found that the lower levels of GABA in patients were responsible for this behavioral abnormality.

"The link between changes in patients' brain chemistry and the cognitive impairments they experience never has been shown before in this way," Carter said. "This work provides tremendous support for targeting the GABA system for treatment of cognitive decline in schizophrenia."

Other study authors include Richard Maddock, Michael Minzenberg, and J. Daniel Ragland of UC Davis, and Ariel Rokem and Michael Silver of the University of California, Berkeley, School of Optometry and Helen Wills Neuroscience Institute.

The study was funded by grants from the National Alliance for Research on Schizophrenia and Depression (NARSAD) and a grant from the National Institute of Health's National Institute of Mental Health.

The underlying causes of the debilitating psychiatric disorder schizophrenia remain poorly understood. In a new study published online March 2, 2010 in Genome Research, however, scientists report that a powerful gene network analysis has revealed surprising new insights into how gene regulation and age play a role in schizophrenia.

Researchers are actively working to identify the direct cause of schizophrenia, likely rooted in interactions between genes and the environment resulting in abnormal gene expression in the central nervous system. Scientists have been studying expression changes in schizophrenia on an individual gene basis, yet this strategy has explained only a portion of the genetic risk.

In the new work, a team of researchers led by Associate Professor Elizabeth Thomas of The Scripps Research Institute has taken a novel approach to this problem, performing a gene network-based analysis that revealed surprising insight into schizophrenia development.

The group analyzed gene expression data from the prefrontal cortex, a region of the brain associated with schizophrenia, sampled post-mortem from normal individuals and schizophrenia patients ranging from 19 to 81 years old. However, instead of just looking at genes individually, Thomas and colleagues at the Scripps Translational Science Institute, Nicholas Schork and Ali Torkamani, considered interactions between genes, as well as groups of genes that showed similar patterns of expression, to identify dysfunctional cellular pathways in schizophrenia.

"Once gene co-expression networks are identified," said Thomas, "we can then ask how they are affected by factors such as age or drug treatment, or if they are associated with particular cell types in the brain."

The gene network analysis suggested that normal individuals and schizophrenia patients have an unexpectedly similar connectivity between genes, but the most surprising finding was a significant link between aging and gene expression patterns in schizophrenia. The team identified several groups of co-expressed genes that behaved differently in schizophrenia patients compared to normal subjects when age was considered.

A particularly striking age-related difference in co-expression was found in a group of 30 genes related to developmental processes of the nervous system. Normally these genes are turned off as a person ages, but in schizophrenia patients the genes remain active. This critical finding strongly suggests that age-related aberrant regulation of genes important for development can explain at least part of the manifestation of schizophrenia.

Thomas explained that these findings help to refine the developmental hypothesis of schizophrenia, which states that one or more pathogenic "triggers" occur during critical periods of development to increase risk of the disease. Specifically, this work indicates that abnormal gene expression in developmentally related genes might be a significant pathogenic trigger, occurring over a broader time-scale than expected.

"Rather than a pathological trigger occurring at a critical developmental time point," said Thomas, "the trigger is ongoing throughout development and aging."

Furthermore, Thomas noted that the new study supports early intervention and treatment of schizophrenia. Treatment approaches aimed at averting gene expression changes and altering the course of the disease could be specifically tailored to the age of the patient.

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Journal Reference:

1. Torkamani A, Dean B, Schork NJ, Thomas EA. Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Coexpression network analysis of neural tissue reveals perturbations in developmental processes in schizophrenia. Genome Research, Published online March 2, 2010 DOI: 10.1101/gr.101956.109

— In reports of two new studies, researchers led by Johns Hopkins say they have identified the mechanisms rooted in two anatomical brain abnormalities that may explain the onset of schizophrenia and the reason symptoms don't develop until young adulthood. Both types of anatomical glitches are influenced by a gene known as DISC1, whose mutant form was first identified in a Scottish family with a strong history of schizophrenia and related mental disorders. The findings could lead to new ways to treat, prevent or modify the disorder or its symptoms.

In one of the studies, published in the March issue of Nature Neuroscience, researchers examined DISC1's role in forming connections between nerve cells. Numerous studies have suggested that schizophrenia results from abnormal connectivity. The fact that symptoms typically arise soon after adolescence, a time of massive reorganization of connections between nerve cells, supports this idea.

The scientists began their study by surveying rat nerve cells to see where DISC1 was most active. Unsurprisingly, they found the highest DISC1 activity in connections between nerve cells. To determine what DISC1 was doing in this location, the researchers used a technique called RNA interference to partially shut off DISC1 activity. Consequently, they saw a transient increase and eventual reduction in size and number of dendritic spines, spikes on nerve cells' branch-like extensions that receive input from other nerve cells.

To determine how DISC1 regulates dendritic spine formation, the researchers studied which brain proteins interact with the protein expressed by the DISC1 gene. They identified one, called Kal-7, which earlier studies suggested is critical for proper dendritic spine formation. Further experiments suggested that the DISC1 protein acts as temporary holding place for Kal-7, binding it until it can be released to trigger a molecular cascade that results in dendritic spine formation.

Study leader Akira Sawa, M.D., Ph.D., professor of psychiatry and director of the program in molecular psychiatry at the Johns Hopkins University School of Medicine, says it is becoming clear that having a defective DISC1 gene might lead to an abnormally small number and size of dendritic spines, which could lead nerve cells to maintain weaker connections with unusually low numbers of neighboring neurons. Such abnormal connectivity has long been seen in autopsied brains from schizophrenia patients.

"Connections between neurons are constantly being made and broken throughout life, with a massive amount of broken connections, or 'pruning,' happening in adolescence," Sawa says. "If this pruning doesn't happen correctly, it may be one reason for the pathogenesis of schizophrenia," he adds.

In the second study, published in the Feb. 25 issue of Neuron, Sawa's team generated a new animal model of schizophrenia by temporarily shutting off the DISC1 gene in mice in the prefrontal cortex, a brain area known to differ in schizophrenic people. The new model allowed them to study other roles for DISC1 in the brain.

The researchers created their novel model by, again, using RNA interference. They injected short pieces of the nucleic acid RNA engineered to shut off the DISC1 gene into cavities in the developing brains of mouse fetuses two weeks after conception. Tests showed that these snippets of RNA migrated into cells in the prefrontal cortex, part of the brain located near the forehead.

This shutoff was temporary, with the gene's function fully restored within three weeks, or about a couple of weeks after birth. At various times after the gene was reactivated, the scientists examined the animals' brains and behavior, looking for differences from normal mice.

Sawa's team found that in the DISC1 shutoff group, nerve cells in the prefrontal cortex that produce dopamine, one of the chemical signals that nerve cells use to communicate, were markedly immature as the animals entered adolescence. Furthermore, the animals showed signs of a deficit of interneurons, nerve cells that connect other neurons in neural pathways.

They also found several behavioral differences between these mice compared to normal mice as the animals entered adolescence. For example, those in the shutoff group reacted more strongly to stimulants, displaying more locomotion than normal mice. Interestingly, these effects were somewhat mitigated when the researchers gave the animals clozapine, a drug used to treat schizophrenia.

Taken together, Sawa says, results of both studies suggest that these anatomical differences, which seem to be influenced by the DISC1 gene, cause problems that start before birth but surface only in young adulthood.

"If we can learn more about the cascade of events that lead to these anatomical differences, we may eventually be able to alter the course of schizophrenia. During adolescence, we may be able to intervene to prevent or lessen symptoms," Sawa says.

Other Johns Hopkins researchers who participated in the Nature Neuroscience study include Akiko Hayashi-Takagi, Manabu Takaki, Saurav Seshadri, Yuichi Makino, Anupamaa J. Seshadri, Koko Ishizuka, Jay M. Baraban, and Atsushi Kamiya. Other Johns Hopkins researchers who participated in the Neuron study include Minae Niwa, Atsushi Kamiya, Hanna Jaaro-Peled, Saurav Seshadri, Hideki Hiyama, and Beverly Huang

A genetic link between schizophrenia and autism is enabling researchers to study the effectiveness of drugs used to treat both illnesses.

Dr Steve Clapcote from the University of Leeds's Faculty of Biological Sciences will be analysing behaviour displayed by mice with a genetic mutation linked to schizophrenia and autism and seeing how antipsychotic drugs affect their behavioural abnormalities.

"We don't fully understand how the drugs used to treat schizophrenia and some symptoms of autism work," explained Dr Clapcote. "If we can show they can affect mice with this particular genetic mutation, then it gives us a clue to better understand the illnesses and opens up the possibility of more targeted treatments with fewer side effects."

A number of autism and schizophrenia patients have been found to have mutations of neurexin 1a, a protein which helps to form and maintain nerve signals in the brain. Scientists in the USA recently discovered that mice with the same genetic mutation display behavioural abnormalities which are consistent with schizophrenia and autism.

Dr Clapcote is planning to build on these initial findings to provide further evidence for a genetic link to the conditions. He also aims to assess the impact on the mice of antipsychotic drugs used to treat schizophrenia and some symptoms of autism.

"The genetic studies so far are suggesting a common cause for both schizophrenia and autism, which is something our studies will help to establish," said Dr Clapcote. "However, these illnesses are complex, involving not only inheritance, but other factors such as environment and experience. It's possible the genetic mutation might create a predisposition, making people more likely to develop autism or schizophrenia."

The mice will be run through a series of tests designed to assess behaviour related to autism and/or schizophrenia: hyperactivity, sensitivity to psychostimulants, attention levels, memory, social interaction and learning. Dr Clapcote will also look at verbal communication — using bat recorders to 'listen' to the interaction between the mice which takes place beyond the range of human hearing.

"Behaviour is the final output of the nervous system and the means by which autism and schizophrenia are diagnosed, which is why our research focuses on behaviour," said Dr Clapcote. "Schizophrenia and autism patients both display lower levels of verbal communication and we hope to see this mirrored in the mice we're working with."

The two-year project has been funded by a £250,000 grant from the Medical Research Council. If the research proves successful, Dr Clapcote plans to investigate a proposed link between neurexin 1a and nicotine dependence, as a possible explanation for why a large percentage of schizophrenia patients become dependent on tobacco.

Schizophrenia is an incredibly complex and profoundly debilitating disorder that typically manifests in early adulthood but is thought to arise, at least in part, from pathological disturbances occurring during very early brain development. Now, a new study published by Cell Press in the February 25 issue of the journal Neuron, manipulates a known schizophrenia susceptibility gene in the brains of fetal mice to begin to unravel the complex link between prenatal brain development and maturation of information processing and cognition in adult animals.

"Although it is clear that multiple factors are involved in schizophrenia, many studies have suggested that variations in disease susceptibility genes might contribute to disruption of high brain functions such as cognition and information processing," explains study author Dr. Akira Sawa from the Department of Psychiatry at the Johns Hopkins School of Medicine in Baltimore. "These genetic factors are believed to be good probes to explore mechanistic links between brain development and adult brain functions."

Dr. Sawa, coauthor Dr. Toshitaka Nabeshima from the Department of Clinical Pharmacology at Meijo University in Nagoya, Japan, and their colleagues showed that a transient reduction of one of the susceptibility genes linked with schizophrenia (Disrupted-in-Schozophrenia-1) in the mouse prefrontal cortex just before or after birth led to aberrant changes in adult animals that are associated with schizophrenia, including perturbation of specific dopaminergic brain pathways, disruption of neural circuitry, and severe behavioral abnormalities.

These findings were significant because they provided a concrete link between a nonlethal genetic disruption during prenatal brain development and specific abnormalities in adult brain maturation. "Prior to our study, the kinds of neurodevelopmental defects that cause the defined anatomical changes observed in schizophrenia patients, clinical onset 15-30 years after birth, psychosis, impaired cognition and information processing and aberrant dopaminergic neurotransmission were not clear," offers Dr. Nabeshima. "However, the model in our study represents a majority of these characteristics."

The authors are careful to caution that while their findings shed some light on how early disease-associated events impact adult brain function, manipulation of one gene cannot fully define the complex neuropathology associated with schizophrenia. "Although it is only one piece of the puzzle, our study may aid molecular understanding of how the initial insults during early development disturb postnatal brain maturation for many years, which results in full-blown onset of schizophrenia or other mental disorders after puberty," explains Dr. Sawa.

The researchers include Minae Niwa, Johns Hopkins University School of Medicine, Baltimore, MD, Meijo University, Nagoya, Japan, Nagoya University Graduate School of Medicine, Nagoya, Japan, Atsushi Kamiya, Johns Hopkins University School of Medicine, Baltimore, MD; Rina Murai, Meijo University, Nagoya, Japan, Nagoya University Graduate School of Medicine, Nagoya, Japan; Ken-ichiro Kubo, Keio University School of Medicine, Tokyo, Japan; Aaron J. Gruber, University of Maryland School of Medicine, Baltimore, MD; Kenji Tomita, Keio University School of Medicine, Tokyo, Japan; Lingling Lu, Meijo University, Nagoya, Japan; Shuta Tomisato, Keio University School of Medicine, Tokyo, Japan; Hanna Jaaro-Peled, Johns Hopkins University School of Medicine, Baltimore, MD; Saurav Seshadri, Johns Hopkins University School of Medicine, Baltimore, MD; Hideki Hiyama, Johns Hopkins University School of Medicine, Baltimore, MD; Beverly Huang, Johns Hopkins University School of Medicine, Baltimore, MD; Kazuhisa Kohda, Keio University School of Medicine, Tokyo, Japan; Yukihiro Noda, Meijo University, Nagoya, Japan; Patricio O'Donnell, University of Maryland School of Medicine, Baltimore, MD; Kazunori Nakajima, Keio University School of Medicine, Tokyo, Japan; Akira Sawa, Johns Hopkins University School of Medicine, Baltimore, MD; and Toshitaka Nabeshima, Meijo University, Nagoya, Japan, Nagoya University Graduate School of Medicine, Nagoya, Japan, The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Nagoya, Japan.

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Journal Reference:

1. Niwa et al. Knockdown of DISC1 by In Utero Gene Transfer Disturbs Postnatal Dopaminergic Maturation in the Frontal Cortex and Leads to Adult Behavioral Deficits. Neuron, 2010; 65 (4): 480-489 DOI: 10.1016/j.neuron.2010.01.019

For the first time, researchers from the University of Pennsylvania School of Medicine have found that three different degenerative brain disorders are linked by a toxic form of the same protein. The protein, called Elk-1, was found in clumps of misshaped proteins that are the hallmarks of Parkinson's disease, Alzheimer's disease, and Huntington's disease.

"These results suggest a molecular link between the presence of inclusions and neuronal loss that is shared across a spectrum of neurodegenerative disease," notes senior author, James Eberwine, PhD, co-director of the Penn Genome Frontiers Institute and the Elmer Holmes Bobst Professor of Pharmacology. "Identifying these links within the diseased microenvironment will open up novel avenues for therapeutic intervention. For example it is reasonable to now ask, "Is this molecule a possible new biomarker for these neurodegenerative diseases?" says Eberwine.

Eberwine, co-first authors Anup Sharma, an MD-PhD student, Jai-Yoon Sul, PhD, Assistant Professor of Pharmacology, both from Penn, Linda M. Callahan, PhD, from the University of Rochester Medical Center, and colleagues, report their findings this week in the online journal PLoS One.

Neurodegenerative diseases are characterized by a number of features including the protein clumps called inclusions; decline of nerve-cell synapses; and the selective loss of the nerve cells themselves.

Elk-1 resides within multiple brain areas, both in the nucleus and the cell body. Interestingly, when it is present in extensions of nerve cells called dendrites, it can initiate the death of that neuron. With this in mind the team assessed whether there is a specific dendrite form of Elk-1 or a modified form called phospho-Elk-1 (pElk-1) that might be associated with a spectrum of human neurodegenerative diseases.

First, they determined the importance of this specific modification of Elk-1 on its ability to initiate regionalized cell death. This was accomplished through site-directed mutations and insertion of the mutated Elk-1 mRNA into dendrites and cell bodies. These studies showed that a specific position on the protein could be modified in the dendrite to cause neuronal cell death.

Next, they screened tissue from a post-mortem human brain bank, specifically samples representative of the three major neurodegenerative diseases, to look for higher levels of the toxic form of Elk-1 protein and compared their findings to levels in brain tissue from age-matched control samples.

By comparing the immunoreactivity for the pElk-1 protein in diseased tissue versus control tissue, they found that pElk-1 strongly associates with the pathological markers present in cases of Parkinson's disease, Alzheimer's disease, and Huntington's disease versus disease-free tissue.

The team hopes to next expand these preliminary findings to a larger sample size of tissues from neurodegenerative disease banks, and to screen blood samples from affected individuals to assess the biomarker capacity of this form of Elk-1 and to use animal models of these illnesses to assess the biological role of this modified form of Elk-1 in the disease processes. They also will be looking for other sites of toxic changes on the Elk-1 protein and will look in other disease tissue for modified Elk-1.

The study was funded by the National Institute on Aging and the National Institute of Mental Health.