Neuroscience
Month
New research in The FASEB Journal suggests that dysfunction in the SRGAP3 protein may lead to schizophrenia, hydrocephalus, mental retardation and some forms of autism in childhood
A new research discovery has the potential to revolutionize the biological understanding of some childhood psychiatric disorders. Specifically, scientists have found that when a single protein involved in brain development, called “SRGAP3,” is malformed, it causes problems in the brain functioning of mice that cause symptoms that are similar to some mental health and neurological disorders in children. Because this protein has similar functions in humans, it may represent a “missing link” for several disorders that are part of an illness spectrum. In addition, it offers researchers a new target for the development of treatments that can correct the biological cause rather than treat the symptoms. This discovery was published in November 2012 print issue of The FASEB Journal.
"Developmental brain disorders such as schizophrenia, hydrocephalus, mental retardation and autism are among the most devastating diseases in children and young adults," said Dusan Bartsch, Ph.D., a researcher involved in the work from the Department of Molecular Biology at the Central Institute of Mental Health at the University of Heidelberg in Mannheim, Germany. "We hope that our findings will contribute to a better understanding, and in the end, to better treatments for these disorders."
Bartsch and colleagues made this discovery using mice with the SRGAP3 protein inactivated. Then they conducted several experiments comparing these mice to normal mice. The mice with inactive SRGAP3 showed clear changes in their brains’ anatomy, which resulted in altered behavior similar to certain symptoms in human neurological and psychiatric diseases. An involvement of SRGAP3 in different brain disorders could indicate that these disorders are possibly connected, as SRGAP3 is a key player in brain development. These different disorders could be connected via the SRGAP3 protein because they all emerge from disturbed development of the nervous system.
"Since Freud put biological psychiatry on the map, we’ve slowly increased our understanding of how mental health is dictated by chemistry," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "Eventually we’ll understand the complex biology underlying most psychiatric illnesses, from genes to proteins to cell signaling to overt behaviors. Along the way, as in this report, we’re likely to find single targets close to the roots of apparently different mental illnesses."
(Image: bzztbomb)
Researchers at the University of Minnesota’s Center for Magnetic Resonance Research (CMRR) have found a small population of neurons that is involved in measuring time, which is a process that has traditionally been difficult to study in the lab.
In the study, which is published October 30 in the open access journal PLOS Biology, the researchers developed a task in which monkeys could only rely on their internal sense of the passage of time. Their task design eliminated all external cues which could have served as “clocks”.
The monkeys were trained to move their eyes consistently at regular time intervals without any external cues or immediate expectation of reward. Researchers found that despite the lack of sensory information, the monkeys were remarkably precise and consistent in their timed behaviors. This consistency could be explained by activity in a specific region of the brain called the lateral intraparietal area (LIP). Interestingly, the researchers found that LIP activity during their task was different from activity in previous studies that had failed to eliminate external cues or expectation of reward.
"In contrast to previous studies that observed a build-up of activity associated with the passage of time, we found that LIP activity decreased at a constant rate between timed movements," said lead researcher Geoffrey Ghose, Ph.D., associate professor of neuroscience at the University of Minnesota. "Importantly, the animals’ timing varied after these neurons were more, or less, active. It’s as if the activity of these neurons was serving as an internal hourglass."
By developing a model to help explain the differences in timing signals they see relative to previous studies, their study also suggests that there is no “central clock” in the brain that is relied upon for all tasks involving timing. Instead, it appears as though each of the brain’s circuits responsible for different actions are capable of independently producing an accurate timing signal.
One important direction for future research is to explore how such precise timing signals arise as a consequence of practice and learning, and whether, when the signals are altered, there are clear effects on behavior.
In the largest prospective study to date of children with early and later manifestation of autism spectrum disorders (ASD) compared to children without ASD, researchers found two distinct patterns of language, social and motor development in the children with ASD. Published in the journal Child Development, the study found that early in development, children who display early signs of ASD show greater initial delay across multiple aspects of development compared to children whose ASD symptoms emerge later. However at 36 months of age, the early differences between these groups are no longer obvious. By the third birthday, the level of impairment between these symptom onset groups of children with ASD is comparable. Additionally, researchers uncovered a preclinical phase of ASD in which the signs of delay are not easily detected with existing clinical tests.
Previous research by Kennedy Krieger Institute researchers found that approximately half of all children with ASD can be diagnosed around the first birthday, while the remaining half do not show diagnostic indicators until later. The current study builds upon these findings by further evaluating motor and language development in a wider age span of children diagnosed with ASD (6 to 36 months), and examining how development unfolds differently in each group.
“Regardless of diagnosis, the development of children with and without ASD appears similar at six months of age on clinical tests,” says Dr. Rebecca Landa, lead author and director of Kennedy Krieger’s Center for Autism and Related Disorders. “However, for those children who went on to develop autism, the earliest signs of atypical development were non-specific to autism, such as general communication or motor delay.”
Why does shock therapy beat back depression? New experiments show how such a blunt treatment can have such positive effects.
Ian Reid, a psychiatrist at the Royal Cornhill Hospital in the Scottish city of Aberdeen, has treated people with severe depression for 25 years. “It’s a very nasty illness, depression,” he says. “I have worked with people who have cancer and depression, and more than one of them has said, ‘If I had to choose one of those two diseases, I’d go for the cancer.’ ”
When patients come to Royal Cornhill with major depression, they’re first treated with psychotherapy and antidepressants. Only about 40 percent respond to their first medication. Sometimes a different one will do the trick, but in Reid’s experience, about 10 to 20 percent of depressed people respond to no drug at all. In those cases, Reid regularly shifts to a third option. It’s officially called electroconvulsive therapy, or ECT—better known by its unofficial name, shock therapy.
Reid is an expert on ECT, and over the years he has received plenty of grief for it. “There are people on the Internet who describe me as a Nazi, as a barbarian,” he says. “And there’s one person who suggested I should get ECT so I know what I’m doing.”
Reid is not surprised by the reactions. For many people, the sum of their knowledge about ECT comes from the 1975 movie One Flew Over the Cuckoo’s Nest. Jack Nicholson plays Randle McMurphy, a criminal hoping to escape hard labor by spending his term in a mental institution. But McMurphy gets more than he bargained for, including a harrowing session of ECT. The hospital staff straps him down, puts a piece of rubber in his mouth so he won’t bite off his own tongue, and delivers a blast of electricity to his temples. He writhes in agony and then slumps back, his body limp.
That scene bears no resemblance to what Reid does for his patients. For one thing, he gives them anesthesia and muscle relaxants so they don’t experience any flailing. But most crucially, ECT works. “You can watch someone going from being unresponsive and soiling themselves to being completely transformed,” Reid says.
In Scotland, a country of 5 million, 400 people receive the treatment each year. And for about 75 percent of them, it brings relief. “ECT outperforms psychotherapeutic treatments and antidepressant drugs,” Reid notes. Yet its effectiveness is a mystery. “It doesn’t sound intuitive at all,” he admits. “Making someone have a seizure, giving them an electric shock, and making something as complex as depression better just seems crazy.”
There is a long history of research on impaired eye movements associated with schizophrenia. Using a series of simple viewing tests, researchers of a new paper in Biological Psychiatry explored the ability of these eye movement tests to distinguish people with and without the diagnosis of schizophrenia.
Using their complete dataset, they were able to develop a model that could discriminate all schizophrenia cases from healthy control subjects with an impressive 98.3% accuracy.
Drs. Philip Benson and David St. Clair, lead authors on the paper, agreed that their findings were remarkable: “It has been known for over a hundred years that individuals with psychotic illnesses have a variety of eye movement abnormalities, but until our study, using a novel battery of tests, no one thought the abnormalities were sensitive enough to be used as potential clinical diagnostic biomarkers.”
Their battery of tests included smooth pursuit, free-viewing, and gaze fixation tasks. In smooth pursuit, people with schizophrenia have well-documented deficits in the ability to track slow-moving objects smoothly with their eyes. Their eye movements tend to fall behind the moving object and then catch-up with the moving object using a rapid eye movement, called a saccade.. A picture is displayed in the free-viewing test, and where most individuals follow a typical pattern with their gaze as they scan the picture, those with schizophrenia follow an abnormal pattern. In a fixation task, the instruction is to keep a steady gaze on a single unmoving target, which tends to be difficult for individuals with schizophrenia.
As expected, the researchers found that the performance of individuals with schizophrenia was abnormal compared to the healthy volunteer group on each of the eye tests. At right is an example of the differences, with the eye tracking of a schizophrenia case in red and a healthy control in blue.
The researchers then used several methods to model the data. The accuracy of each of the created algorithms was then tested by using eye test data from another group of cases and controls. Combining all the data, one of the models achieved 98.3% accuracy.
"It is encouraging to see the high sensitivity of this model for the diagnosis of schizophrenia. It will be interesting to see the extent to which this approach enables clinical investigators to distinguish people with schizophrenia from individuals with other psychiatric disorders," commented Dr. John Krystal, Editor of Biological Psychiatry.
Benson and St Clair have already started that work, stating, “We now have exciting unpublished data showing that patterns of eye movement abnormalities are specific to different psychiatric subgroups, another key requirement for diagnostic biomarkers. The next thing we want to know is when the abnormalities are first detectable and can they be used as disease markers for early intervention studies in major mental illness?”
"We are also keen to explore how best our findings can be developed for use in routine clinical practice," they added. Typical neuropsychological assessments are time-consuming, expensive, and require highly trained individuals to administer. In comparison, these eye tests are simple, cheap, and take only minutes to conduct. This means that a predictive model with such precision could potentially be incorporated in clinics and hospitals to aid physicians by augmenting traditional symptom-based diagnostic criteria.
Scientists at Freie Universität, Universität Hohenheim, and Katholieke Universiteit Leuven Breed Fruit Flies for First Time without the Neurobeachin Protein and Facilitate Study of Nervous Diseases in Humans
In experiments on the brain of the fruit fly Drosophila, scientists at Freie Universität Berlin have advanced the research on brain function and diseases in humans. Neuroscientists in the Emmy Noether Junior Research Group “Biological Memory Systems” headed by Dr. Martin Schwärzel and based at Freie Universität succeeded in breeding fruit flies without the neurobeachin protein. Among other things, BEACH proteins affect the development and function of the brain in animals and humans. The results were published in the most recent issue of The Journal of Neuroscience. In the future such animal models could be of particular importance for the understanding of certain diseases in humans, such as autism. Scientists from the University of Hohenheim and the Belgian Katholieke Universiteit Leuven were also involved.
Up to now there were no animal models suitable for understanding the significance of neurobeachin proteins in the functioning of the nervous system, for example in memory formation. Mice that are lacking the neurobeachin protein die shortly after birth. Fruit flies, on the other hand, can be alive and well without neurobeachin. The scientists also found in experiments on the flies that neurobeachin has a function in learning as the flies exhibit characteristic learning disabilities due to the absence of the protein.
The flies were also found to have a number of other abnormalities with regard to the development and function of the nervous system. Through a “genetic rescue experiment,” the researchers were able to localize the distribution of these defects in the brain. The function of the lacking neurobeachin gene was reintroduced in certain areas of the nervous system. With this procedure, the researchers were able to show, among other things, that certain features of the neurobeachin protein in flies and mice are identical.