Posts tagged schizophrenia
Articles and news from the latest research reports.
Finding the perfect balance — regulating brain activity to improve attention
Researchers from The University of Nottingham have found that balanced activity in the brain’s prefrontal cortex is necessary for attention.
The research helps to make sense of attention deficits in people suffering from cognitive disorders — like schizophrenia — who often find it hard to sustain their attention. This has a significant effect on many aspects of their lives, including the ability to follow conversations, drive a car and hold down a job.
Activity in a healthy brain is controlled by inhibitory signals between neurons. The research shows that disrupting this healthy inhibition may be just as bad for attention as reducing neuron firing. It is often assumed that increasing brain activity has cognitive benefits, but the findings show that this is not always the case.
The research was carried out by a team in the University’s School of Psychology and involved inhibiting or disinhibiting the prefrontal cortex in rats and monitoring the effect. The researchers found that both of these extremes resulted in attentional deficits and that the ability to pay attention required an appropriate balance where neuron-firing was kept within a certain range.
Schizophrenia and attention deficits
Studies of the brain in people with schizophrenia suggest aberrant neuron-firing in the prefrontal cortex. There is evidence that neuron firing in this part of the brain is often too high or too low.
Dr Tobias Bast, who led the study together with first author Dr Marie Pezze, said: “The implication of our findings is that the abnormalities we see in the prefrontal cortex of schizophrenia patients, for example, are indeed a plausible cause of the attention deficit these patients have.
“It also means that if we want to treat this pharmacologically, we can’t just boost activity of the prefrontal cortex or inactivate it, because that would actually result in an impairment. What we need to do is look at restoring balance of activity through drugs which keep the activity within a certain range.”
Cognitive deficits associated with schizophrenia
In people with schizophrenia, cognitive deficits — such as problems with attention — are less striking than other issues associated with the disorder, such as hallucinations, but are nevertheless a major problem.
Dr Bast said: “Initially people focused on the so-called ‘psychotic symptoms’, including hallucinations and delusions, so that’s what probably comes to mind when you think of schizophrenia. They have been in the fore because they have been so striking and that’s why referrals are made. But these can be treated, at least in a large proportion of patients, by using anti-psychotic medication, which we have had since the late 1950s.
“The problem is that unfortunately anti-psychotic drugs don’t improve cognitive deficits which are very debilitating, affecting many aspects of the patients’ lives. Cognitive deficits are a big problem and something that is currently not treated so finding something that helps this is really important.”
Study shows increasing rates of premature death and violent crime in people with schizophrenia since 1970s
New research, published in The Lancet Psychiatry journal, shows that rates of adverse outcomes, including premature death and violent crime, in people with schizophrenia are increasing, compared to the general population.
The results come from a unique study, led by Dr Seena Fazel, at Oxford University, UK, which analyses long-term adverse outcomes – including conviction for a violent crime (such as homicide or bodily harm) premature death (before the age of 56), and death by suicide – between 1972 and 2009 in nearly 25,000 people in Sweden diagnosed with schizophrenia or related disorders.
For the first time, the researchers compared adverse outcomes in people with a diagnosis of schizophrenia to both the general population and to unaffected siblings, allowing them to account for risk factors within families (such as parental criminality or violence) which might be expected to affect the risk of suicide or violent behaviour in siblings.
Overall, the results show that within five years of diagnosis, around 1 in 50 men and women with schizophrenia (2.3% of men and 1.7% of women) died by suicide; around one in 10 (10.7%) of men and around one in 37 (2.7%) of women with schizophrenia were convicted of a violent offence within five years of diagnosis. Overall, men and women with schizophrenia were eight times more likely to die prematurely than the general population.
Analysing the changing rate of adverse outcomes across the study period (1972 – 2009), the researchers found that the risk of premature death, suicide, and conviction for a violent offence has increased for men and women with schizophrenia in the last 38 years, compared with both the general population, and their unaffected siblings.
By tracking the number of nights spent in hospital by people with schizophrenia during the study period, the study shows that these increased rates of adverse outcomes appear to be associated with decreasing levels of inpatient care for these patients, although the study does not provide any evidence for a causal connection between decreasing inpatient care and adverse outcomes.
The researchers also analysed risk factors for adverse outcomes in both people with schizophrenia, the general population, and unaffected siblings. Across all three groups, the risk factors for violence and premature death were broadly similar, and included drug use disorders, criminality, and self-harm, all before diagnosis – suggesting that improved strategies to address these risk factors have the potential to reduce violence and premature deaths across the population, and not just in those with schizophrenia.
According to Dr Fazel, “In recent years, there has been a lot of focus on primary prevention of schizophrenia – preventing people from getting ill. While primary prevention is clearly essential and may be some decades away, our study highlights the crucial importance of secondary prevention – treating and managing the risks of adverse outcomes, such as self-harm or violent behaviour, in patients. Risks of these adverse outcomes relative to others in society appear to be increasing in recent decades, suggesting that there is still much work to be done in developing new treatments and mitigating risks of adverse outcomes in people with schizophrenia.”*
Dr Eric Elbogen and Sally Johnson, at the University of North Carolina-Chapel Hill School of Medicine, USA, write in a linked Comment that, “One of the unique aspects of this study—that violence and suicide were analysed simultaneously—has an important implication for how we as a society perceive people with mental illness. News coverage of schizophrenia and other psychiatric disorders often focuses on violence and crime. Much less attention is paid to suicide and self-harm in people with severe mental illnesses.”
However, they add that, “Importantly, we should remember that, when reporting about the intricate links between schizophrenia and these adverse outcomes, most people with schizophrenia and related disorders are neither violent nor suicidal. Despite the need to ensure people with schizophrenia are provided help to reduce their risks of suicide, violence, or premature death, researchers reporting findings also bear the burden of ensuring that most people with schizophrenia and related disorders, who are not violent, are not left to contend with stigma and discrimination. Policy makers, researchers, and clinicians need to remember the importance of appropriately weighing up the issue of schizophrenia relative to the myriad of other factors that contribute to increased risk of violence and suicide.”
(Source: alphagalileo.org)
Uncovering Clues to the Genetic Cause of Schizophrenia
The overall number and nature of mutations—rather than the presence of any single mutation—influences an individual’s risk of developing schizophrenia, as well as its severity, according to a discovery by Columbia University Medical Center researchers published in the latest issue of Neuron. The findings could have important implications for the early detection and treatment of schizophrenia.
Maria Karayiorgou, MD, professor of psychiatry and Joseph Gogos, MD, PhD, professor of physiology and cellular biophysics and of neuroscience, and their team sequenced the “exome”—the region of the human genome that codes for proteins—of 231 schizophrenia patients and their unaffected parents. Using this data, they demonstrated that schizophrenia arises from collective damage across several genes.
“This study helps define a specific genetic mechanism that explains some of schizophrenia’s heritability and clinical manifestation,” said Dr. Karayiorgou, who is acting chief of the Division of Psychiatric and Medical Genetics at the New York State Psychiatric Institute. “Accumulation of damaged genes inherited from healthy parents leads to higher risk not only to develop schizophrenia but also to develop more severe forms of the disease.”
Schizophrenia is a severe psychiatric disorder in which patients experience hallucination, delusion, apathy and cognitive difficulties. The disorder is relatively common, affecting around 1 in every 100 people, and the risk of developing schizophrenia is strongly increased if a family member has the disease. Previous research has focused on the search for individual genes that might trigger schizophrenia. The availability of new high-throughput DNA sequencing technology has contributed to a more holistic approach to the disease.
The researchers compared sequencing data to look for genetic differences and identify new loss-of-function mutations—which are rarer, but have a more severe effect on ordinary gene function—in cases of schizophrenia that had not been inherited from the patients’ parents. They found an excess of such mutations in a variety of genes across different chromosomes.
Using the same sequencing data, the researchers also looked at what types of mutations are commonly passed on to schizophrenia patients from their parents. It turns out that many of these are “loss-of-function” types. These mutations were also found to occur more frequently in genes with a low tolerance for genetic variation.
“These mutations are important signposts toward identifying the genes involved in schizophrenia,” said Dr. Karayiorgou.
The researchers then looked more deeply into the sequencing data to try to determine the biological functions of the disrupted genes involved in schizophrenia. They were able to verify two key damaging mutations in a gene called SETD1A, suggesting that this gene contributes significantly to the disease.
SETD1A is involved in a process called chromatin modification. Chromatin is the molecular apparatus that packages DNA into a smaller volume so it can fit into the cell and physically regulates how genes are expressed. Chromatin modification is therefore a crucial cellular activity.
The finding fits with accumulating evidence that damage to chromatin regulatory genes is a common feature of various psychiatric and neurodevelopmental disorders. By combining the mutational data from this and related studies on schizophrenia, the authors found that “chromatin regulation” was the most common description for genes that had damaging mutations.
“A clinical implication of this finding is the possibility of using the number and severity of mutations involved in chromatin regulation as a way to identify children at risk of developing schizophrenia and other neurodevelopmental disorders,” said Dr. Gogos. “Exploring ways to reverse alterations in chromatic modification and restore gene expression may be an effective path toward treatment.”
In further sequencing studies, the researchers hope to identify and characterize more genes that might play a role in schizophrenia and to elucidate common biological functions of the genes.
(Image caption: These images show the movement of patient-derived neural progenitor cells from a sphere of neurons in a migration assay. How far and quickly the neurons move indicates whether they may behave atypically in the brain. Credit: Courtesy of the Salk Institute for Biological Studies)
New stem cell research points to early indicators of schizophrenia
Using new stem cell technology, scientists at the Salk Institute have shown that neurons generated from the skin cells of people with schizophrenia behave strangely in early developmental stages, providing a hint as to ways to detect and potentially treat the disease early.
The findings of the study, published online in April’s Molecular Psychiatry, support the theory that the neurological dysfunction that eventually causes schizophrenia may begin in the brains of babies still in the womb.
"This study aims to investigate the earliest detectable changes in the brain that lead to schizophrenia," says Fred H. Gage, Salk professor of genetics. "We were surprised at how early in the developmental process that defects in neural function could be detected."
Currently, over 1.1 percent of the world’s population has schizophrenia, with an estimated three million cases in the United States alone. The economic cost is high: in 2002, Americans spent nearly $63 billion on treatment and managing disability. The emotional cost is higher still: 10 percent of those with schizophrenia are driven to commit suicide by the burden of coping with the disease.
Although schizophrenia is a devastating disease, scientists still know very little about its underlying causes, and it is still unknown which cells in the brain are affected and how. Previously, scientists had only been able to study schizophrenia by examining the brains of patients after death, but age, stress, medication or drug abuse had often altered or damaged the brains of these patients, making it difficult to pinpoint the disease’s origins.
The Salk scientists were able to avoid this hurdle by using stem cell technologies. They took skin cells from patients, coaxed the cells to revert back to an earlier stem cell form and then prompted them to grow into very early-stage neurons (dubbed neural progenitor cells or NPCs). These NPCs are similar to the cells in the brain of a developing fetus.
The researchers generated NPCs from the skin cells of four patients with schizophrenia and six people without the disease. They tested the cells in two types of assays: in one test, they looked at how far the cells moved and interacted with particular surfaces; in the other test, they looked at stress in the cells by imaging mitochondria, which are tiny organelles that generate energy for the cells.
On both tests, the Salk team found that NPCs from people with schizophrenia differed in significant ways from those taken from unaffected people.
In particular, cells predisposed to schizophrenia showed unusual activity in two major classes of proteins: those involved in adhesion and connectivity, and those involved in oxidative stress. Neural cells from patients with schizophrenia tended to have aberrant migration (which may result in the poor connectivity seen later in the brain) and increased levels of oxidative stress (which can lead to cell death).
These findings are consistent with a prevailing theory that events occurring during pregnancy can contribute to schizophrenia, even though the disease doesn’t manifest until early adulthood. Past studies suggest that mothers who experience infection, malnutrition or extreme stress during pregnancy are at a higher risk of having children with schizophrenia. The reason for this is unknown, but both genetic and environmental factors likely play a role.
"The study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage," says Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
Kristen Brennand, the first author of the paper and assistant professor at Icahn School of Medicine at Mount Sinai, said the researchers were surprised that the skin-derived neurons remained in such an early stage of development. “We realized they weren’t mature neurons but only as old as neurons in the first trimester,” Brennand says. “So we weren’t studying schizophrenia but the things that go wrong a long time before patients actually get sick.”
Interestingly, the study also found that antipsychotic medication such as clozapine and loxapine did not improve migration in NPCs (in particular, loxapine actually worsened migration in these cells).
"That was an experiment that gave the opposite results from what we were expecting," says Brennand. "Though in hindsight, using drugs that treat symptoms might not be helpful in trying to prevent the disease."
The next steps to this work will be to increase the sample size to a broader range of patients and to look at hundreds or thousands of patient samples, says Brennand.
Ιn resting brains, Yale researchers see signs of schizophrenia
In an advance that increases hopes of finding biological markers for schizophrenia, Yale researchers have discovered widespread disruption of signals while the brain is at rest in those suffering from the disabling neuropsychiatric disease.
The Yale team used fMRI scans and created a mathematical model that simulates brain activity to discover the disruptions in global signaling — or patterns of neurological activity while the brain is not involved in any particular task. Previously, many researchers had thought that the overall brain activity at rest was mostly “background noise” and not clinically important, said Alan Anticevic, assistant professor in psychiatry at the Yale School of Medicine and senior author of the study, reported online May 5 in the Proceedings of the National Academy of Sciences. “To our knowledge these results provide the first evidence that global whole-brain signals are altered in schizophrenia, calling into question the standard removal of this signal in clinical neuroimaging studies,” Anticevic said.
These novel results have vital and broad implications for neuroimaging, as the search for neuropsychiatric biomarkers that could lead to early intervention and improved patient outcomes remains a prominent focus outlined by the National Institute of Mental Health.
Research in the News: Brain at rest yields clues to origins of mental illness
While at rest, multiple regions of the brain remain engaged in a highly heritable, stable pattern of activity called the default mode network. Researchers have found that this network is often disrupted in people with schizophrenia and bipolar disorder, which appear to share underlying genetic causes. This network is often abnormal in their unaffected close relatives, suggesting common genetic roots.
Now researchers at the Yale University School of Medicine and the Institute of Living in Hartford have devised a method to simultaneously identify many genes that play a role in disrupting this network. “Previous studies have identified small numbers of different genes which each contribute in a small way to schizophrenia and bipolar disorder but tell us little overall about the development of psychosis in an individual,” said Godfrey Pearlson, professor of psychiatry and neurobiology and senior author of the study. “Now we have begun to identify markers for these conditions that consist of hundreds of such genes acting simultaneously in recognized pathways that will eventually help in our designing novel ways to intervene in the disease process.”
The study was published April 28 in the Proceedings of the National Academy of Sciences.
Protein researchers closing in on the mystery of schizophrenia
Seven per cent of the adult population suffer from schizophrenia, and although scientists have tried for centuries to understand the disease, they still do not know what causes the disease or which physiological changes it causes in the body. Doctors cannot make the diagnosis by looking for specific physiological changes in the patient’s blood or tissue, but have to diagnose from behavioral symptoms.
In an attempt to find the physiological signature of schizophrenia, researchers from the University of Southern Denmark have conducted tests on rats, and they now believe that the signature lies in some specific, measurable proteins. Knowing these proteins and comparing their behaviour to proteins in the brains of not-schizophrenic people may make it possible to develop more effective drugs.
It is extremely difficult to study brain activity in schizophrenic people, which is why researchers often use animal models in their strive to understand the mysteries of the schizophrenic brain. Rat brains resemble human brains in so many ways that studying them makes sense if one wants to learn more about the human brain.
Schizophrenic symptoms in rats
The strong hallucinogenic drug phenocyclidine (PCP), also known as “angel’s dust”, provides a range of symptoms in people which are very similar to schizophrenia.
“When we give PCP to rats, the rats become valuable study objects for schizophrenia researchers,” explains Ole Nørregaard Jensen, professor and head of the Department of Biochemistry and Molecular Biology.
Along with Pawel Palmowski, Adelina Rogowska-Wrzesinska and others, he is the author of a scientific paper about the discovery, published in the international Journal of Proteome Research.
Among the symptoms and reactions that can be observed in both humans and rats are changes in movement and reduced cognitive functions such as impaired memory, attention and learning ability.
"Scientists have studied PCP rats for decades, but until now no one really knew what was going on in the rat brains at the molecular level. We now present what we believe to be the largest proteomics data set to date," says Ole Nørregaard Jensen.
PCP is absorbed very quickly by the brain, and it only stays in the brain for a few hours. Therefore, it was important for researchers to examine the rats’ brain cells soon after the rats were injected with the hallucinogenic drug.
"We could see changes in the proteins in the brain already after 15 minutes. And after 240 minutes, it was almost over," says Ole Nørregaard Jensen.
The University of Southern Denmark holds some of the world’s most advanced equipment for studying proteins, and Ole Nørregaard Jensen and his colleagues used the university’s so-called mass spectrometres for their protein studies.
352 proteins cause brain changes
"We found 2604 proteins, and in 352 of them, we saw changes that can be associated with the PCP injections. These 352 proteins will be extremely interesting to study in closer detail to see if they also alter in people with schizophrenia - and if that’s the case, it will of course be interesting to try to develop a drug that can prevent the protein changes that lead to schizophrenia," says Ole Nørregaard Jensen about the discovery and the work that now lies ahead.
The 352 proteins in rat brains responded immediately when the animals were exposed to PCP. Roughly speaking, the drug made proteins turn on or off when they should not turn on and off. This started a chain reaction of other disturbances in the molecular network around the proteins, such as changes in metabolism and calcium balance.
"These 352 proteins are what causes the rats to change their behaviour - and the events are probably comparable to the devastating changes in a schizophrenic brain," explains Ole Nørregaard Jensen.
The protocol for studying rat brain proteins with mass spectrometry, developed by Ole Nørregaard Jensen and his colleagues, is not limited to schizophrenia studies - it can also be used to explore other diseases.
The research was a collaboration between the University of Southern Denmark, the Danish Technological Institute and NeuroSearch A/S.
Details about the experiment
Twelve rats were used for the experiment. Six received an injection with the hallucinogenic drug PCP (10 mg/kg body weight), and six were injected with a saline solution to serve as controls. After 15 minutes, the first two animals in each group were killed and within less than two minutes, samples of their brains (temporal lobes) were taken and quickly frozen in liquid nitrogen.
After 30 and 240 minutes, respectively, the same was done to other rats. All experiments were conducted in accordance with Danish and EU guides for the handling of laboratory animals. The collected tissue samples were then subjected to various mass spectrometric protein analyses. The analyses revealed differences in the phosphorylation of proteins indicating which proteins had been affected by the drug PCP.
Interpretation of the complex protein data set suggest that PCP affects a number of processes in brain cells and leads to changes in calcium balance in the brain cells, changes in the transport of substances into and out of cells, changes in cell metabolism and changes in the structure of the cell’s internal skeleton, the cytoskeleton.
Schizophrenia: What’s in my head?
When she’s experiencing hallucinations, artist Sue Morgan feels compelled to draw; to ‘get it out of her head’. Sue was diagnosed with schizophrenia about 20 years ago. The drawing is therapeutic, but it’s also Sue’s way of expressing the complex and sometimes frightening secret world in her head. In this film Sue meets Sukhi Shergill, a clinician and researcher at the Institute of Psychiatry in London. He’s also making pictures, but using MRI to peer inside the brains of schizophrenia patients.
Read more about schizophrenia
Noisy brain signals: How the schizophrenic brain misinterprets the world
People with schizophrenia often misinterpret what they see and experience in the world. New research provides insight into the brain mechanisms that might be responsible for this misinterpretation. The study from the Montreal Neurological Institute and Hospital – The Neuro - at McGill University and McGill University Health Centre, reveals that certain errors in visual perception in people with schizophrenia are consistent with interference or ‘noise’ in a brain signal known as a corollary discharge. Corollary discharges are found throughout the animal kingdom, from bugs to fish to humans, and they are thought to be crucial for monitoring one’s own actions. The study, published in the April 2 issue of the Journal of Neuroscience, identifies a corollary discharge dysfunction in schizophrenia, which could aid with diagnosis and treatment of this difficult disorder. It was carried out in collaboration with researchers Veronica Whitford, Gillian O’Driscoll, and Debra Titone in the Department of Psychology, McGill University.
“A corollary discharge is a copy of a nervous system message that is sent to other parts of the brain, in order to make us aware that we are doing something,” said Dr. Christopher Pack, neuroscientist at The Neuro and lead investigator on the study. “For example, if we want to move our arm, the motor area of the brain sends a signal to the muscles to produce a movement. A copy of this command, which is the corollary discharge, is sent to other regions of the brain, to inform them of the impending movement. If you were moving your arm, and you didn’t have the corollary discharge signal, you might assume that someone else was moving your arm. Similarly, if you generated a thought, and you had an impaired corollary discharge, then you might assume that someone else placed the thought in your mind. Corollary discharges ensure that different areas of the brain are communicating with each other, so that we are aware that we are moving our own arm, talking, or thinking our own thoughts.”
Schizophrenia is a disorder that interferes with the ability to think clearly and to manage emotions. People with schizophrenia often attribute their own thoughts and actions to external sources, as in the case of auditory hallucinations. Other common symptoms include delusions and disorganized thinking and speech.
Recent research has suggested that an impaired corollary discharge can account for some of these symptoms. However, the nature of the impairment was unknown. In their study, Dr. Pack and his colleagues (including Dr. Alby Richard, neurology resident at The Neuro) used a test called a perisaccadic localization task, to investigate corollary discharge activity. In this test, subjects are asked to make quick eye movements to follow a dot on a computer screen. At the same time they are also asked to localize visual stimuli that appear briefly on the screen from time to time. In order to perform this task accurately, subjects need to know where on the screen they are looking – in other words they use corollary discharges signals that arise from the brain structures that control the eye muscles.
The results showed that people with schizophrenia were less accurate in figuring out where they were looking. Consequently they made more mistakes in estimating the position of the stimuli that were flashed on the screen. “What is interesting and potentially clinically important is that the pattern of mistakes made by the patients correlated with the extent of their symptoms,” said Dr. Pack. “This is particularly interesting because the circuits that control eye movements include the best-understood structures in the brain. So we are optimistic that we can work backward from the behavioral data to the biological basis of the corollary discharge effects. We have already started to do this with computational modeling. Mathematically we can convert the corollary discharge of a healthy control into the corollary discharge of a patient with schizophrenia by adding noise and randomness. It is not that people with schizophrenia have no corollary discharge, or a corollary discharge with delayed or weaker amplitude. Rather the patients appear primarily to have a noisy corollary discharge signal. This visual test is very easy thing to do and quite sensitive to individual differences.“
The study shows that patients with schizophrenia make larger errors in localizing visual stimuli compared to controls. These results could be explained by a corollary discharge signal, which also predicts patient symptom severity, suggesting a possible basis for some of the most common symptoms of schizophrenia. This work was supported by The Natural Sciences and Engineering Research Council of Canada, The Brain & Behavior Research Foundation (NARSAD) and the EJLB Foundation.
Experimental Cancer Drug Reverses Schizophrenia in Adolescent Mice
Johns Hopkins researchers say that an experimental anticancer compound appears to have reversed behaviors associated with schizophrenia and restored some lost brain cell function in adolescent mice with a rodent version of the devastating mental illness.
The drug is one of a class of compounds known as PAK inhibitors, which have been shown in animal experiments to confer some protection from brain damage due to Fragile X syndrome, an inherited disease in humans marked by mental retardation. There also is some evidence, experts say, suggesting PAK inhibitors could be used to treat Alzheimer’s disease. And because the PAK protein itself can initiate cancer and cell growth, PAK inhibitors have also been tested for cancer.
In the new Johns Hopkins-led study, reported online March 31 in the Proceedings of the National Academy of Sciences, the researchers found that the compound, called FRAX486, appears to halt an out-of-control biological “pruning” process in the schizophrenic brain during which important neural connections are unnecessarily destroyed.
Working with mice that mimic the pathological progression of schizophrenia and related disorders, the researchers were able to partially restore disabled neurons so they could connect to other nerve cells.
The Johns Hopkins team says the findings in teenage mice are an especially promising step in efforts to develop better therapies for schizophrenia in humans, because schizophrenia symptoms typically appear in late adolescence and early adulthood.
“By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit,” says study leader Akira Sawa, M.D., Ph.D., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine. “That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing.”
For the mouse experiments, Sawa and his colleagues chemically turned down the expression of a gene known as Disrupted-in-Schizophrenia 1 (DISC1), whose protein appears to regulate the fate of neurons in the cerebral cortex responsible for “higher-order” functions, like information processing.
In studies of rodent brain cells, the researchers found that a DISC1 deficit caused deterioration of vital parts of the neuron called spines, which help neurons communicate with one another.
Reduced amounts of DISC1 protein also impact the development of a protein called Kalirin-7 (KAL7), which is needed to regulate another protein called Rac1. Without enough DISC1, KAL7 can’t adequately control Rac1 production and the development of neuronal spines. Excess Rac1 apparently erases spines and leads to excess PAK in the mice.
By using FRAX486 to reduce the activity of PAK, the researchers were able to protect against the deterioration of the spines caused by too little DISC1, halting the process. This normalized the excess pruning and resulted in the restoration of missing spines. They were able to see this by peering into the brains of the mice with DISC1 mutations on the 35th and 60th day of their lives, the equivalent of adolescence and young adulthood.
Sawa, who is also director of the Johns Hopkins Schizophrenia Center, cautions that it has not yet been shown that PAK is elevated in the brains of people with schizophrenia. Thus, he says, it is important to validate these results by determining whether this haywire PAK cascade is also occurring in humans.
In the mice, the researchers also found that their behavior improved when PAK inhibitors were used. The mice were tested for their reaction to noises. There is a neuropsychiatric phenomenon in which any organism will react less to a strong, startling sound when they have first been primed by hearing a weaker one. In schizophrenia, the first noise makes no impact on the reaction to the second one.
The mice in the study showed improvements in their reactions after being treated with the PAK inhibitor. The drug was given in small doses and appeared to be safe for the animals.
“Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage,” Sawa says. “This compound has the potential to do both.”
(Image: iStockphoto)