Close study of key autism genes suggests a potential treatment approach

In adult mice that have lost CHD8 gene function, the FDA-approved drug partially restores disrupted brain cell production.

CincinnatiAnd the September 23, 2022 /PRNewswire/ — Research led by a scientist at Cincinnati Children’s Hospital who primarily studies brain tumors may open doors to better treatment for autism.

Autism spectrum disorder (ASD) affects 1 in 40 children between the ages of 3 and 17, according to the National Survey of Children’s Health. Affected people often have difficulty with social communication, impaired language development, repetitive behaviors, and other symptoms. Of those tested for different genes associated with the condition, nearly everyone had devastating gene mutations. CHD8 He has autism.

Now studying led Ching Richard Lu, Ph.D., Beatrice C. Lampkin Chair in Cancer Epigenetics and Scientific Director of brain tumor center In Cincinnati Children’s, he sheds new light on the role CHD8 It plays in brain development — during embryonic development and much later during adulthood. the studypublished September 23, 2022In the Journal of Neurosciencealso reports that FDA-approved antidepressants fluoxetine (marketed as Prozac) partially restores lost brain cell production, also known as neurogenesis, in mice lacking CHD8.

“This is an exciting first step, but we need to further confirm these results with further studies in a variety of mouse models,” Lu says. “In the long term, it will also require large-scale clinical trials before the treatment is approved for human use.”

From cancer to autism

Lou is a highly respected expert in brain tumors 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 something went wrong CHD8 The genes can disrupt the formation of the myelin sheaths that protect and support rapid signals between neurons in the brain and central nervous system. Then the team started wondering how CHD8 It affects how neurons form themselves.

Among the many details in the study, the researchers found that the effects caused by the disorder CHD8 Function varies greatly depending on when the disturbance occurred. In mice, when CHD8 Absent from the start, brain development is deeply affected, particularly in the formation of the cortex, the area that controls social behavior, thinking, and problem-solving, and the hippocampus that supports learning and memory. Many fetuses with this early genetic deletion show severe brain defects. mice with loss CHD8 A function in the brain that develops many of the classic autistic behaviors, including avoidance of others. The effect was surprising when mapping the movements of normal and lost control mice CHD8 working as adults.

However, gene function can also be disrupted at other points of development, whether it is during late pregnancy, youth, or puberty. The team found ways to induce these disorders in mice at different life stages, then analyzed the effects. In adult mice, CHD8 Loss also impairs neurogenesis from precursor neurons.

With Prozac being one of the most widely studied antidepressants, the team already knew that the drug had been found to stimulate the growth of neurons. When they gave medicine to mice with CHD8 They found that neuron production had resumed. The recovery wasn’t complete but it was powerful enough that the drug deserves closer study as a potential way to increase neurogenesis in the brain CHD8Deficiency, says Lu.

The next step: more behavior tests

Lu’s lab is now working on extensive research involving multiple strains of mice that have been developed to mimic ASD conditions. They analyze changes in behavior against varying doses and time points for treatment, and more.

Three members of Lu’s lab were the first co-authors of this study: Chen DongAnd the Chuntao ZhaoAnd the Xiang Chen. Several other fellows from the Departments of Development Biology, Experimental Hematology and Cancer Biology contributed. Collaborators also included scientists with Fudan University Children’s Hospital, Shanghai, Chinaand the University of California San Francisco.

This study was funded by a Cincinnati Children’s Research Foundation Award and a National Institutes of Health Training Grant (2T32CA117846-11A1).

Source: Cincinnati Children’s Hospital Medical Center