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Discovery of a ‘Neuronal Big Bang’

Mon, 03/07/2016 - 11:07am University of Geneva This is an expression of all the genes of a neuron during the first hours after its birth. Each circle represents a development stage (6h, 12h, 24h), and the colored points within each circle represent the level of gene expression. (Credit: Jabaudon Lab/ UNIGE)Our brain is home to different types of neurons, each with their own genetic signature that defines their function. These neurons are derived from progenitor cells, which are specialized stem cells that have the ability to divide to give rise to neurons. Neuroscientists from the Faculty of Medicine at the University of Geneva (UNIGE) shed light on the mechanisms that allow progenitors to generate neurons. By developing a novel technology called FlashTag that enables them to isolate and visualize neurons at the very moment they are born, they have deciphered the basic genetic code allowing the construction of a neuron. This discovery, which is published in Science, allows not only to understand how our brain develops, but also how to use this code to reconstruct neurons from stem cells. Researchers will now be able to better understand the mechanisms underlying neurological diseases such as autism and schizophrenia.Directed by Denis Jabaudon, a neuroscientist and neuroscientist at the Department of Basic Neurosciences at UNIGE Faculty of Medicine and neurologist at the University Hospitals Geneva (HUG), the researchers developed a technology termed FlashTag, which visualizes neurons as they are being born. Using this approach, at the very moment where a progenitor divides, it is tagged with a fluorescent marker that persists in its progeny. Scientists can then visualize and isolate newborn neurons in order to dynamically observe which genes are expressed in the first few hours of their existence. [...]

Receptors in brain linked to schizophrenia, autism

Mice lacking a set of receptors in one type of neuron in the brain developed compulsive, anti-social behaviors, Salk scientists found August 11, 2015 LA JOLLA–The loss of a critical receptor in a special class of inhibitory neurons in the brain may be responsible for neurodevelopmental disorders including autism and schizophrenia, according to new research by Salk scientists. The importance of the receptor, called mGluR5, in other areas of the brain had been previously established. Until now, however, no one had studied their specific role in a cell type known as parvalbumin-positive interneurons, thought to be important in general cognition and generating certain types of oscillatory wave patterns in the brain. “We found that without this receptor in the parvalbumin cells, mice have many serious behavioral deficits,” says Terrence Sejnowski, head of Salk’s Computational Neurobiology Laboratory, which led the research published in Molecular Psychiatry on August 11, 2015. “And a lot of them really mimic closely what we see in schizophrenia.” When mice are engineered to lack the mGluR5 receptor in parvalbumin cells (right), they have fewer inhibitory (red) connections controlling the activity of excitatory neurons. Click here for a high-resolution image. Image: Courtesy of the Salk Institute for Biological Studies Scientists had previously discovered that when molecular signaling was disrupted in these cells during development, the brain’s networks didn’t form correctly. Separate studies have revealed that mGluR5 receptors, which transmit glutamate signaling in the brain, are linked to addiction disorders, anxiety and Fragile X Syndrome. But, in these cases, mGluR5 is affected in excitatory cells, not inhibitory cells like the parvalbumin-positive interneurons. The Salk team wondered what the role of mGluR5 was in the parvalbumin cells since the cells were deemed so important in [...]

Focus on Research: Research gives new hope for restoring cells in damaged brains and spinal cords

An artist's rendition of a human spinal cord. Credit: EMSL CREATIVE COMMONS LICENSE Centre Daily Times (CDT), January 17, 2015 — What motivates Penn State scientists and their students to devote countless hours trying to solve tough research mysteries? For Gong Chen, a biology professor at Penn State, the answer is rooted in a desire to help relieve the suffering of patients and their loved ones. “I want to help people who are suffering from injuries and diseases of the brain and spinal cord,” he told a crowd of Alzheimer’s patients and their friends and family at Medlar Field at Lubrano Park. During the Alzheimer’s Association’s Walk to End Alzheimer’s Disease in October, the crowd broke into applause, cheers and some tears when Chen announced his lab’s most recent research achievement. “We have developed a revolutionary approach for reversing scarred tissues inside the brain back into normal neural tissue,” he said. Chen, who is Penn State’s Verne M. Willaman Chair in the Life Sciences, directs a research team that is working on simultaneous research projects related to brain and spinal-cord disorders. These disorders include Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, traumatic brain injury, spinal-cord injury, epilepsy, autism and schizophrenia. The lab’s technique for repairing scarred tissues in the brain is the latest in a recent series of discoveries that have been published by highly respected scientific journals including Cell, Nature, Cell Stem Cell and Nature Communications, among others. The brain has neuronal cells, called neurons, and another kind called glial cells. When glial cells are healthy, they are important components of the brain’s nervous system. Healthy glial cells surround neurons — the brain’s nerve cells — and provide them with support, protection, insulation, oxygen [...]

Schizophrenia not a single disease but multiple genetically distinct disorders

Washington University in St. Louis, by Jim Dreyden ~ September 15, 2014 New research shows that schizophrenia isn’t a single disease but a group of eight genetically distinct disorders, each with its own set of symptoms. The finding could be a first step toward improved diagnosis and treatment for the debilitating psychiatric illness. The research at Washington University School of Medicine in St. Louis is reported online Sept. 15 in The American Journal of Psychiatry. About 80 percent of the risk for schizophrenia is known to be inherited, but scientists have struggled to identify specific genes for the condition. Now, in a novel approach analyzing genetic influences on more than 4,000 people with schizophrenia, the research team has identified distinct gene clusters that contribute to eight different classes of schizophrenia. “Genes don’t operate by themselves,” said C. Robert Cloninger, MD, PhD, one of the study’s senior investigators. “They function in concert much like an orchestra, and to understand how they’re working, you have to know not just who the members of the orchestra are but how they interact.” Cloninger, the Wallace Renard Professor of Psychiatry and Genetics, and his colleagues matched precise DNA variations in people with and without schizophrenia to symptoms in individual patients. In all, the researchers analyzed nearly 700,000 sites within the genome where a single unit of DNA is changed, often referred to as a single nucleotide polymorphism (SNP). They looked at SNPs in 4,200 people with schizophrenia and 3,800 healthy controls, learning how individual genetic variations interacted with each other to produce the illness. Robert Boston Igor Zwir, PhD, one of the senior investigators, helped match precise DNA variations in people with and without schizophrenia to symptoms in individual patients. [...]

Genetic mapping triggers new hope on schizophrenia

R&D, by Seth Borenstein, AP Writer ~ July 23, 2014 Scientists have linked more than 100 spots in our DNA to the risk of developing schizophrenia, casting light on the mystery of what makes the disease tick. Such work could eventually point to new treatments, although they are many years away. Already, the new results provide the first hard genetic evidence to bolster a theory connecting the immune system to the disease. More than 100 researchers from around the world collaborated in the biggest-ever genomic mapping of schizophrenia, for which scientists had previously uncovered only about a couple of dozen risk-related genes. The study included the genetic codes of more than 150,000 people—nearly 37,000 of them diagnosed with the disease. Researchers found 108 genetic markers for risk of getting the disease, 83 of them not previously reported. And scientists say there are still likely more to be found. "It's a genetic revelation; schizophrenia has been a mystery," said study co-author Steve McCarroll, director of genetics for the Broad Institute of MIT and Harvard. "Results like this give you things to work on. It takes it out of the zone of guesses about which genes are relevant." The results were released Monday by the journal Nature. It takes large studies to ferret out genes related to schizophrenia risk because each gene generally has only a very weak effect. Schizophrenia is a debilitating mental disorder that makes it hard to tell the difference between what is real and not real, and affects about one out of every 100 people. Studies estimate that it costs $60 billion in the U.S. each year. Scientists have long known that genes play a part, and this work further confirms that. The [...]

Uncovering Clues to the Genetic Cause of Schizophrenia

Bioscience Technology, Source: Columbia University Medical Center ~ May 29, 2014 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 study 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 [...]

New target explored for psychiatric drug development

Washington University in St. Louis, by Jim Dryden In a surprising discovery, neuroscientists have found that a breakdown product of cholesterol in the brain may be a target for developing new drugs to treat schizophrenia and other mental illnesses. Although the research is in its early stages, the finding comes at a crucial time. Most existing drugs to treat schizophrenia work in similar ways, targeting dopamine receptors in the brain, but many patients don’t respond well to the medications or can’t tolerate the side effects. The investigators, from Washington University School of Medicine in St. Louis, SAGE Therapeutics and Weill Cornell Medical College, report in The Journal of Neuroscience that a molecule known as an oxysterol helps control a different type receptor in the brain that is key in cognitive function. Because the naturally occurring oxysterol molecule interacts with receptors not normally associated with medications used to treat serious psychiatric illnesses, the researchers believe it could be useful in the development of new types of antipsychotic drugs. The molecule, called 24(S)-hydroxycholesterol, targets NMDA receptors in the brain, which are important in processes thought to be the biological underpinnings of learning and memory. Although most existing antipsychotic drugs instead target dopamine receptors, drugs that block NMDA receptor function — such as the anesthetic ketamine and the street drug PCP — can produce psychotic symptoms or relieve depression, depending on the dosage. The researchers believe that molecules that enhance activity in NMDA receptors may help control psychotic symptoms and limit the learning and memory problems that accompany illnesses such as schizophrenia. “One of the big problems for patients with schizophrenia is that they have difficulty with working memory and learning new things,” said principal investigator Charles F. [...]

‘Jumping Genes’ Linked to Schizophrenia

Science Magazine, by Emily Underwood ~ January 2, 2014 Roaming bits of DNA that can relocate and proliferate throughout the genome, called "jumping genes," may contribute to schizophrenia, a new study suggests. These rogue genetic elements pepper the brain tissue of deceased people with the disorder and multiply in response to stressful events, such as infection during pregnancy, which increase the risk of the disease. The study could help explain how genes and environment work together to produce the complex disorder and may even point to ways of lowering the risk of the disease, researchers say. Schizophrenia causes hallucinations, delusions, and a host of other cognitive problems, and afflicts roughly 1% of all people. It runs in families—a person whose twin sibling has the disorder, for example, has a roughly 50-50 chance of developing it. Scientists have struggled to define which genes are most important to developing the disease, however; each individual gene associated with the disorder confers only modest risk. Environmental factors such as viral infections before birth have also been shown to increase risk of developing schizophrenia, but how and whether these exposures work together with genes to skew brain development and produce the disease is still unclear, says Tadafumi Kato, a neuroscientist at the RIKEN Brain Science Institute in Wako City, Japan and co-author of the new study. Over the past several years, a new mechanism for genetic mutation has attracted considerable interest from researchers studying neurological disorders, Kato says. Informally called jumping genes, these bits of DNA can replicate and insert themselves into other regions of the genome, where they either lie silent, doing nothing; start churning out their own genetic products; or alter the activity of their neighboring genes. If [...]

Schizophrenia Tied To Abnormal Memory Network In Brain

Red Orbit, by Alan McStravick ~ October 16, 2013 Individuals suffering with schizophrenia are subject to a whole host of disturbing, life-changing symptoms. They can range from disorganized thinking and an inability to plan for the future to full-on hallucinations and paranoid delusions. Through treatment with psychiatric therapy and medication can be effective for some, the psychiatric disease has largely remained a medical mystery. However, researchers at the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT have uncovered what they term “a faulty brain mechanism” they believe is crucial in the eventual development of schizophrenia and other psychiatric disorders in humans. Speaking about the study published in today’s issue of Neuron, Susumu Tonegawa, director at RIKEN-MIT said, “Our study provides new insight into what underlies schizophrenia’s disordered thinking and zeroes in on a new target for future investigation into the neural basis of a cognitive disorder that affects more than 1 percent of the world’s population.” Tonegawa is also a senior author of the study. This study, like many others in the fields of genetics, was an animal study. The team employed the use of genetically engineered mice that displayed symptoms of schizophrenia. One difficulty faced by this study, in particular, was figuring out how to model the complex nature of disorganized thought in the mice. The research team began their study with the understanding that human patients suffering from cognitive disorders will present abnormal neural activity in what is known as the default mode network (DMN). The DMN is a network inclusive of the brain’s prefrontal cortex and the hippocampus. It is in these areas of the brain scientists believe we process memories. As the researchers [...]