Findings should help narrow the search for genetic contributions of autism and suggest new routes for therapy
"Aha" moments are rare in medical research, scientists say. As rare, they add, as finding mice with Mohawk-like hairstyles.
But both events happened in a lab at NYU Langone Medical Center, months after an international team of neuroscientists bred hundreds of mice with a suspect genetic mutation tied to autism spectrum disorders.
Almost all the grown mice, the NYU Langone team observed, had sideways,"overgroomed" hair with a highly stylized center hairline between their ears and hardly a tuft elsewhere. Mice typically groom each other's hair.
Researchers say they knew instantly they were on to something, as the telltale overgrooming — a repetitive motor behavior — had been linked in other experiments in mice to the brain condition that prevents children from developing normal social, behavioral, cognitive, and motor skills. People with autism, the researchers point out, exhibit noticeably dysfunctional behaviors, such as withdrawal, and stereotypical, repetitive movements, including constant hand-flapping, or rocking.
Now and for what NYU Langone researchers believe to be the first time, an autistic motor behavior has been traced to specific biological pathways that are genetically determined.
The findings, says senior study investigator Gordon Fishell, PhD, the Julius Raynes Professor of Neuroscience and Physiology at NYU Langone, could with additional testing in humans lead to new treatments for some autism, assuming the pathways' effects as seen in mice are reversible.
In the study, to be published in the journal Nature online May 25, researchers knocked out production in mice of a protein called Cntnap4. This protein had been found in earlier studies in specialized brain cells, known as interneurons, in people with a history of autism.
Researchers found that knocking out Cntnap4 affected two highly specialized chemical messengers in the brain, GABA and dopamine. Both are so-called neurotransmitters, chemical signals released from one nerve cell to the next to stimulate similar sensations throughout the body. GABA, short for gamma-aminobutyric acid, is the main inhibitory neurotransmitter in the brain. It not only helps control brain impulses, but also helps regulate muscle tone. Dopamine is a well-known hormonal stimulant, highly touted for producing soothing, pleasing sensations.
Among the researchers' key findings was that in Mohawk-coiffed mice, reduced Cntnap4 production led to depressed GABA signaling and overstimulation with dopamine. Researchers say the lost protein had opposite effects on the neurotransmitters because GABA is fast acting and quickly released, so interfering with its action decreases signaling, while dopamine's signaling is longer-acting, so impairing its action increases its release.
"Our study tells us that to design better tools for treating a disease like autism, you have to get to the underlying genetic roots of its dysfunctional behaviors, whether it is overgrooming in mice or repetitive motor behaviors in humans," says Dr. Fishell. "There have been many candidate genes implicated in contributing to autism, but animal and human studies to identify their action have so far not led to any therapies. Our research suggests that reversing the disease's effects in signaling pathways like GABA and dopamine are potential treatment options."
The U.S. Centers for Disease Control and Prevention estimate that one in 68 American children under age 8 has some form of autism, with five times as many boys as girls suffering from the spectrum of disorders.
As part of their study, researchers performed dozens of genetic, behavioral, and neural tests with growing mice to isolate and pinpoint where Cntnap4 acted in their brains, and how it affected chemical signaling among specific interneuron brain cells, which help relay and filter chemical signals between neurons in localized areas of the brain.
They found that Cntnap4 in mature interneurons strengthened GABA signaling, but did not do so in younger interneurons. When researchers traced where Cntnap4 acted in immature brain cells, Dr. Fishell says tests showed that it stimulated "a big bolus of dopamine."
As part of testing to confirm the hereditary link among Cntnap4, the two pathways, and grooming behaviors, researchers exposed young mice with normal levels of Cntnap4, who did not groom each other, to mature mice with and without Cntnap4. Only mature mice deficient in Cntnap4 preened the hairstyle on other mice. Further tests in young mice without Cntnap4 showed that other, mature mice with normal amounts of Cntnap4 largely let them be, without any particular grooming or hairstyle.
Dr. Fishell and his team plan further analyses of how GABA and dopamine production changes as brain cells mature, and precisely what cellular mechanisms are involved in autism. Their goal is to control and rebalance any biological systems that go awry, as a possible future therapy for the disease.
Funding support for the study was provided by the Simons Foundation, the National Institute for Mental Health, and the National Institute of Neurological Disorders and Stroke, both members of the US National Institutes of Health. Corresponding federal grant numbers are R01 NS081297, R01 MH071679, R01 NS074972, P01 NS074972, R01 NS036362, R01 DA033811, NS30989, NS30989, and NS50220. Study funding was also supported by grants from the Attilio and Olympia Ricciardi Research Fund, the Israel Science Foundation, as well as through postdoctoral fellowships from the Patterson Trust and Roche Inc., the New York State NYSTEM initiative, and the Canadian Institutes of Health Research.
Besides Dr. Fishell, other NYU Langone researchers involved in this study were Theofanis Karayannis, DPhil; Edmund Au, PhD; Jyoti Patel, PhD; Ilya Kruglikov, PhD; Bernardo Rudy, MD, PhD; Margaret Rice, PhD; Charles Hoeffer, PhD; and Richard Tsien, DPhil. Additional research support was provided by Sander Markx, MD; Laura Rodriguez-Murillo, PhD; and Maria Karayiorgou, MD, at Columbia University in New York City; Joseph Glessner, PhD, at the Children's Hospital of Philadelphia; Richard Delorme, PhD; Hakon Hakonarson, MD, PhD; Guillaume Huguet, PhD; and Thomas Bourgeron, PhD, at L'Institut Pasteur in Paris, France; Delphine Heron, MD; and Boris Keren, MD, at the Groupe Hospitalier La Pitié-Salpêtrière, also in Paris, France; and Aaron Gordon, PhD; and Elior Peles, PhD, at the Weizmann Institute of Science in Rehovot, Israel.
For more information, go to:
About NYU Langone Medical Center:
NYU Langone Medical Center, a world-class, patient-centered, integrated academic medical center, is one of the nation's premier centers for excellence in clinical care, biomedical research, and medical education. Located in the heart of Manhattan, NYU Langone is composed of four hospitals—Tisch Hospital, its flagship acute care facility; Rusk Rehabilitation; the Hospital for Joint Diseases, the Medical Center's dedicated inpatient orthopaedic hospital; and Hassenfeld Children's Hospital, a comprehensive pediatric hospital supporting a full array of children's health services across the Medical Center—plus the NYU School of Medicine, which since 1841 has trained thousands of physicians and scientists who have helped to shape the course of medical history. The Medical Center's tri-fold mission to serve, teach, and discover is achieved 365 days a year through the seamless integration of a culture devoted to excellence in patient care, education, and research. For more information, go to http://www.NYULMC.org, and interact with us on Facebook, Twitter, and YouTube.
David March | Eurek Alert!
North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich
Researchers Discover New Anti-Cancer Protein
22.03.2018 | Universität Basel
An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.
The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...
In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.
Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...
Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.
They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...
A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...
For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.
In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...
19.03.2018 | Event News
16.03.2018 | Event News
13.03.2018 | Event News
22.03.2018 | Trade Fair News
22.03.2018 | Earth Sciences
22.03.2018 | Earth Sciences