Enlarged Brain Size Due to More Glia Cells in a Non-human Primate Autism Model

In a study published in Cell Discovery on March 7, 2023, which was performed via collaboration between ZHANG Yong Qing's research team from the Institute of Genetics and Developmental Biology (IGDB) of the Chinese Academy of Sciences and LI Xiaojiang's team from Jinan University, showed that mutations in the CHD8 (chromodomain helicase DNA binding protein 8) gene lead to an abnormal increase in glial cells in cynomolgus monkeys in the early stage of brain development, resulting in large head malformation or macrocephaly.

Autism is a group of neurodevelopmental disorders that affect about 0.7% of children in China. Mutations in the CHD8 gene are closely associated with autism spectrum disorders and were found to be heterozygous, which can lead to macrocephaly that is seen in some individuals with autism. Small animal models have showed inconsistent findings about the mechanism of CHD8 deficiency-mediated macrocephaly. Pathological studies have not been reported in patients with CHD8 mutations. Therefore, the pathogenic mechanism of how CHD8 mutations lead to macrocephaly is unclear.

The proliferation, development, and maturation of neuronal and glial cells determine the formation and volume of the brain. Past studies utilizing mouse models have proposed that macrocephaly is associated with an abnormally increased number of neuronal cells. However, the ratio of glial cells to neural cells in the mouse brain is much lower than that in the primate brain, and glial cells are important for the formation and the function of the primate brain. The non-human primate monkey model is much closer to human in terms of brain structure and function. The researches thus established CHD8 mutant monkeys by CRISPR/Cas9 gene targeting, and found an increased number of glial cells (astrocyte and oligodendrocyte) in the brains of CHD8 mutant monkeys, while the number of neural cells was not significantly affected. This new finding suggests that glial cell overproliferation can cause an increase in the white matter volume of the brain, leading to macrocephaly. Glial cell overproliferation can also impair the function of neural circuits and thus affect the emotional-cognitive function of autistic patients. The study of the CHD8 mutant monkey model provides new ideas and targets for interventions in the early stages of autistic patients.

This study is a new achievement of the collaboration between two teams of Professors ZNANG and LI. Since SHANK3 gene mutation can also cause autism, the two teams previously established the first SHANK3 gene edited monkey model of autism using CRISPR/Cas9 technology in 2017 (published in Cell Research), and found that SHANK3 can specifically regulate primate embryonic brain development. The discovery of the CHD8 mutant monkey model in the present study again underscores the necessity of using non-human primate models to study the pathogenesis of autism.

 

 

Contact:

Prof. ZHANG Yong Qing

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences

Email: yqzhang@genetics.ac.cn