Closer Study of Major Autism Gene Suggests Possible Treatment Approach
In adult mice with loss of CHD8 gene function, FDA-approved drug partially restores disrupted brain cell production
CINCINNATI,Sept. 23, 2022/PRNewswire/ -- Research led by a scientist at Cincinnati Children's who primarily studies brain tumors may open doors for improved treatment of autism.
Autism spectrum disorder (ASD) affects about one in 40 children between ages 3 and 17, according to the National Survey of Children's Health. Those affected often experience difficulty socializing, impaired language development, repetitive behaviors, and other symptoms. Of those tested for various genes linked to the condition, nearly everyone with disruptive mutations of the geneCHD8has autism.
Now a study led byQing Richard Lu, PhD, Beatrice C. Lampkin Endowed Chair in Cancer Epigenetics and Scientific Director of theBrain Tumor Centerat Cincinnati Children's, sheds new light on the roleCHD8plays in brain development—both during embryonic growth and much later during adulthood.The study, publishedSept. 23, 2022, in theJournal of Neuroscience, also reports that the FDA-approved antidepressantfluoxetine(marketed as Prozac) partially restores lost brain cell production, also known as neurogenesis, in mice lackingCHD8.
"This is an exciting first step, but we need to further confirm these findings with more studies in a variety of mouse models," Lu says. "Longer term, it also would require large scale clinical trials before a treatment could be approved for human use."
Lu is a widely respected brain tumor expert who has devoted years to understanding how the brain forms and how brain development can go wrong. In previous work, his lab team became interested in how malfunctioningCHD8genes could disrupt formation of myelin sheaths that protect and support rapid signaling between nerve cells in the brain and central nervous system. Then the team began wondering howCHD8affects how the nerve cells themselves are formed.
Among the many details in the study, the researchers found that the effects caused by disruptedCHD8function vary considerably depending on when the disruption occurs. In mice, whenCHD8is missing from the start, brain development is deeply affected, especially in the formation of the cortex, the area that controls social behavior, thinking and problem-solving, and the hippocampus, which supports learning and memory. Many embryos with this early-stage gene deletion exhibit severe brain defects. The mice with loss ofCHD8大脑功能发展几个经典autistic behaviors, including avoiding others. The effect was striking when mapping the movements of normal control mice and those that had lostCHD8function as adults.
However, the gene's function also can be disrupted at other points of development, be it during late-term pregnancy, youth, or adulthood. The team found ways to cause these disruptions in mice at different age points, then analyzed the effects. In the adult mice,CHD8loss also impairs neurogenesis from neural precursor cells.
With Prozac being one of the most widely studied antidepressants, the team already knew that the drug had been found to stimulate nerve cell growth. When they gave the drug to the mice with theCHD8loss, they found that nerve cell production resumed. The restoration was not complete but was powerful enough that the drug merits closer study as a potential way to augment neurogenesis inCHD8-deficiency, Lu says.
Now Lu's lab is working on expanded research involving multiple lines of mice that have been developed to mimic ASD conditions. They are analyzing changes in behavior against varying doses and timepoints of treatment, and more.
Three members of Lu's lab were co-first authors on this study:Chen Dong,Chuntao Zhao, andXiang Chen.Several other colleagues from the Divisions of Development Biology and Experimental Hematology and Cancer Biology contributed. Collaborators also included scientists with Children's Hospital of Fudan University,Shanghai, China, and theUniversity of California San Francisco.
This study was funded by Cincinnati Children's Research Foundation award and a National Institutes of Health training grant (2T32CA117846-11A1).
SOURCE Cincinnati Children's Hospital Medical Center
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