Unraveling autism

A multifaceted approach aims to detect, treat and even reverse the disorder. BY REBECCA BOYLE, January 3, 2017 Washington University in St. Louis - Like many patients visiting a doctor’s office, Kim Sebenoler started out her appointment by heading to the nearest restroom to give a urine sample. But her visit to the lab of John Constantino, MD, director of the William Greenleaf Eliot Division of Child Psychiatry, was not a typical exam. The goal was not to measure proteins in her urine or check her overall wellness. Instead, researchers took her urine cells to replicate human brain cell function in a Petri dish. The study is one of three major approaches School of Medicine researchers are using to unravel the physical and psychological underpinnings of autism. The unique, multifaceted effort — studying genes, brain activity patterns and behavior — is giving researchers and practitioners a better understanding of the disorder, which today affects one in every 100 Americans. The cells are helping co-investigators Constantino and neuroscientist Azad Bonni, MD, PhD, explore how brain function changes in people with autism spectrum disorder (ASD). Both researchers are international leaders — Constantino in clinical autism studies and Bonni in advancing understanding of the underlying mechanisms of brain development. The Kroll lab has figured out not only how to create neurons, but also to create neuron types that perform specific functions. These types — cortical excitatory neurons and inhibitory neurons — often are abnormal in patients with autism. This process includes a specific chemical treatment to generate these types of neurons in a Petri dish. In this case, populations of neurons are derived from the cells of the Sebenoler family. The Kroll lab has figured out not only [...]

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. [...]

Loss of support cells in brain may inhibit neuronal development

October 6, 2015 By Jim Dryden Washington University School of Medicine researchers Courtney Sobieski (left) and Steven Mennerick, PhD, found, in culture, that without cells called astrocytes, neurons send signals to one another more slowly. That slowdown could interfere with neuronal development and contribute to conditions linked to communication between neurons. Shedding light on possible contributors to autism, schizophrenia and other neuro-psychiatric disorders, researchers have found that a type of support cell abundant in the brain may play a role in the ability of neurons to communicate. The team of scientists, atWashington University School of Medicine in St. Louis found, in culture, that without these cells — called astrocytes — the ability of neurons to send certain signals is slowed. Such a slowdown could interfere with neuronal development and contribute to conditions linked to communication between neurons, including autism and schizophrenia. The study is available in The Journal of Neuroscience. “This work highlights that although neurons are the focus of considerable research, the brain is composed of other types of cells that also are very important,” said first author Courtney Sobieski. “Astrocytes are support cells that appear to play a key role in the development of healthy neurons. The neurons have trouble communicating without the support of astrocytes.” Senior author Steven Mennerick, PhD, professor of psychiatry, explained that glutamate, a neurotransmitter, plays a key role in carrying messages around the brain. “It’s the main transmitter at about 90 percent of the points of communication in the brain,” he said. “And we found that when we take away astrocytes, glutamate signaling is compromised.” Sobieski, a graduate student in Mennerick’s lab, developed a way to grow individual neurons either with or without astrocytes. As they compared the [...]

As CIRM opens world’s largest stem cell bank, scientists ready their research

Sep 1, 2015 A $32 million public-private bank — where California researchers collect stem cells and scientists from around the world can make withdrawals — officially opened Tuesday with the aim of accelerating the use of engineered stem cells to tackle a wide range of diseases. The bank, funded by the California Institute for Regenerative Medicine and located at Novato's Buck Institute for Research on Aging, already is making 300 induced pluripotent stem cell lines available to researchers studying heart, lung, liver and blinding eye diseases as well as epilepsy, autism, cerebral palsy and Alzheimer's Disease. Officials at San Francisco-based CIRM, which is the state's stem cell research funding agency, said the bank is the largest in the world, based on the number of donors, and will have 750 cell lines by February. But it also is a big win for CIRM as critics push the agency to show some bang from the more than $2 billion it has spent since California voters in 2004 approved selling $3 billion in bonds for stem cell research. CIRM in March 2013 approved spending $32 million to create the bank of induced pluripotent stem cells, which are "mature" cells, such as the skin, that are manipulated to return to their embryonic state. At that point, the bank can coax the cells back to a mature state but as heart, liver, skin or any other organ. The process — with major contributions from Nobel Prize winner Shinya Yamanaka of Kyoto University, the Gladstone Institutes and the University of California, San Francisco — means that a researcher isn't required to get true embryonic stem cells from the brain of an autism patient, for example, and can instead get skin cells [...]

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 [...]

Disrupted REM Sleep Can Rewire Young Brains

7/22/15 Cynthia Fox, Science Writer Kittens with eye patches deprived of non-REM (rapid eye movement) sleep do not end up with impaired connections in a visual center of the brain. But kittens deprived of REM sleep do. This is according to a new Science Advances studythat “adds important new data to our understanding of how the complicated state of REM functions in early life,” University of Mississippi associate professor of psychiatry and human behavior James Shaffery, D.Phil., told Bioscience Technology. Shaffery was not involved in the new study. “I was surprised how important REM sleep turned out to be,” senior author Marcos Frank, Ph.D., told Bioscience Technology. Frank is a Washington State University neuroscientist. “I thought other stages of sleep would be key, but I was wrong.  Happily wrong.” The above, with the study’s second finding —that key memories can fail to form in REM-deprived developing brains—indicates that drugs given to children, from antidepressants to stimulants, may need to be intensely analyzed for impact on REM. REM’s biological function Since its discovery as “a third state of being sixty-plus years ago, the biological function of the REM sleep state has remained a bit of a mystery,” Shaffery told Bioscience Technology. Shaffery has extensively studied REM. In the last two decades, understanding has accelerated. “Studies in humans, cats and rats have lent support to the role of the REM sleep state serving important functions in certain forms of memory consolidation and in brain development.” Frank Marcos, Ph.D. of Washington State UniversityEarly work unexpectedly unearthed the fact that human neonates undergo far more REM sleep than adults. “This observation formed the basis of the Ontogenetic Hypothesis of the function of REM sleep that has generated a considerable [...]

NIH joins public-private partnership to fund research on autism biomarkers

Biomarkers Consortium project to improve tools for measuring and treating social impairment in children with autism July 20, 2015 Government, non-profit and other private partners will fund a multi-year project to develop and improve clinical research tools for studying autism spectrum disorder (ASD). The project will receive a total of $28 million over the next four years to test and refine clinical measures of social impairment in ASD in order to better evaluate potential behavioral and drug therapies. It is supported by the National Institutes of Health (NIH), the Foundation for the NIH (FNIH), the Simons Foundation Autism Research Initiative (SFARI), and others.  NIH funding comes from the National Institute of Mental Health (NIMH), the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. “This consortium project will develop reliable tools and measures that clinical researchers can use to assess potential treatments.” —Thomas R. Insel, M.D. NIMH Director The effort is the latest addition to the prestigious list of projects supported by the Biomarkers Consortium , a large public-private partnership that aims to accelerate biomedical research progress. James McPartland Ph.D. of Yale School of Medicine, New Haven, Connecticut, serves as principal investigator. The Consortium supports research to identify disease-specific biomarkers and develop targeted technologies and treatments. Its ultimate goal is precision medicine — an emerging approach to prevention and treatment that takes into account an individual’s disease-related variations in genes, environment, and lifestyle. ASD is a group of neurodevelopmental disorders that affects social interaction and communication skills and can cause restricted and repetitive behaviors. Approximately 1 percent of children throughout the world have an ASD, each with his or her own unique combination of symptoms and [...]

State Funding Gives Providers Access to Telehealth Training for Chronic Diseases

July 02, 2015 - Stephanie Baehman - COLUMBIA, Mo. — Health care providers across the state are now being trained to provide residents in their communities with more specialized treatment for diabetes care, hepatitis C, childhood asthma, dermatology, chronic pain management and autism. Karen Edison, MD The Missouri Telehealth Network has received $1.5 million in state appropriations to develop and launch the Show-Me Extension for Community Healthcare Outcomes (ECHO) program. ECHO projects are being formed throughout the country, but Missouri is the first state to provide funding allowing for numerous ECHO programs to be offered statewide with a centralized training hub at the University of Missouri. An ECHO program works by having a panel of experts in various chronic diseases use video conferencing to train and support primary care providers throughout the state. "ECHO is an added layer to the existing telehealth services in Missouri," said Karen Edison, MD, medical director of the Missouri Telehealth Network, director of the Center for Health Policy and chair of the MU School of Medicine’s Department of Dermatology. "By training primary care providers, we are not only increasing access but also the number of patients who will receive treatment. This allows patients in rural areas to receive care without needing to leave their own community." Keeping patients close to home for treatment provides added economic benefits for communities. Patients can stay in their local area to have medical tests and lab work completed, or have their medications filled at a local pharmacy, all activities that keep health care dollars local. The Missouri Telehealth Network is partnering with other health systems and academic medical centers in the state to provide the most robust programs with experts on a variety of [...]

Preemies at high risk of autism don’t show typical signs of disorder in early infancy

July 1, 2015 By Alex Griffel ROBERT BOSTON PHOTO A small study at Washington University School of Medicine in St. Louis indicates that premature infants who avoid eye contact are less likely to demonstrate symptoms of autism at age 2 than preemies who maintain eye contact during early interactions. ​Premature babies are at an increased risk for developing autism spectrum disorder. But a small study indicates that preemies who avoid eye contact in early infancy are less likely to demonstrate symptoms of autism at age 2 than preemies who maintain eye contact during early interactions, according to new research at Washington University School of Medicine in St. Louis. “Children with autism typically have challenges with social interaction and may avoid eye contact, but it turned out that children in this study who had characteristics of autism at age 2 were more likely to maintain eye contact and not avert their gazes in early infancy,” said first author Bobbi Pineda, PhD, assistant professor in occupational therapy and in pediatrics. The research is available in the July/August issue of The American Journal of Occupational Therapy. Early intervention can benefit children with autism spectrum disorder. However, while signs of autism have been observed in infants as early as two to six months of age, the disorder is difficult to diagnose before age 2. In the new study, the researchers observed behavioral symptoms characteristic of autism in a particularly high-risk group of young children: those born prematurely. Observing early behaviors may give researchers and clinicians indicators to look for early in life so they can recommend timely diagnostic testing and interventions to improve a baby’s adaptive responses and outcome. The researchers evaluated 62 premature infants hospitalized in the neonatal [...]

Low glycemic index diet reduces symptoms of autism in mice

Salk researchers find diet recommended for diabetics ameliorated signs of autism in mice June 09, 2015 LA JOLLA–Bread, cereal and other sugary processed foods cause rapid spikes and subsequent crashes in blood sugar. In contrast, diets made up of vegetables, fruits and whole grains are healthier, in part because they take longer to digest and keep us more even-keeled. New research in a mouse model of autism showed that such low glycemic index diets, similar to the plans that people with diabetes follow to keep their blood sugar in check, reduced symptoms of the disorder in mice. Although preliminary and not yet tested in humans, the findings, published June 9, 2015, in the journal Molecular Psychiatry, might offer clues to understanding one potential cause of autism. The brains of mice fed a high glycemic index diet have greater numbers of activated immune cells (shown in red and green) called microglia. Image: Courtesy of the Salk Institute for Biological Studies The number of people diagnosed with autism–a spectrum of disorders characterized by social avoidance, repetitive behaviors and difficulty communicating–has risen dramatically over the past two decades for reasons that are unclear. More people may be diagnosed due to a broader definition of autism and better efforts in diagnosis, but a true increase in the disorder cannot be ruled out, according to the U.S. Centers for Disease Control. Lifestyle change is one potential factor out of many possible causes of autism. “One thing that’s driving a lot of general physiological changes in people is changes in the diet,” says the study’s corresponding author Pamela Maher, a senior staff scientist in the laboratory of Professor David Schubert at the Salk Institute for Biological Studies. In the new study, [...]