Developmental disorders, including autism, entail challenges in social life; as the number of affected individuals has risen, this has become a significant societal concern. Using a mouse model, we demonstrate that a mutation in CHD8, a gene associated with autism spectrum disorder, causes abnormal differentiation of ventral progenitor cells, leading to autistic-like behavior in adulthood. This should lead to the elucidation of mechanisms underlying autism onset during brain development and to the advancement of therapeutics.
Background
Autism spectrum disorder (hereafter, autism) is a developmental disorder characterized by difficulties with social-interaction and by restricted interests and repetitive behaviors. It has attracted significant attention due to its high prevalence, affecting approximately one in every 36 persons, and symptoms that interfere with daily life. In recent years, genetic mutation analysis targeting individuals with autism has revealed that CHD8 *1) , a chromatin remodeler, is one of the most frequently mutated genes associated with autism, attracting significant attention (Figure 1).
CHD8 is known to be involved in the differentiation and maturation of diverse cells in the brain. It was unknown, however, at which stage of brain development and in which types of cells mutations in the CHD8 gene exert their effects to cause autistic-like behavior.
Results
This study was conducted by a team of researchers from the Institute of Frontier Science Initiative and from the Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University. First, they succeeded in generating mice in which the expression level of CHD8 could be reduced at a specific developmental stage, using gene-editing technology. As a result, it was revealed that mice with reduced CHD8 expression at the midfetal stage (embryonic day 14.5) exhibited autistic-like behavior, such as abnormal social-interaction and anxiety-like behavior, while such behavioral abnormalities were not observed in mice with reduced CHD8 expression at a late fetal stage (embryonic day 17.5) onwards (Figure 2). Furthermore, through gene expression analysis and histological analysis of the brain, they determined that CHD8 mutation at the midfetal stage excessively promoted the differentiation of ventral progenitor cells *2) , thereby causing developmental abnormalities in inhibitory neurons *3) and oligodendrocyte *4) -lineage cells. In addition, using spatial transcriptomics and in vivo neural circuit functional analysis *5) , they revealed that changes in inhibitory neurons associated with CHD8 mutation led to functional abnormalities in neural circuits in the adult brain (Figure 3).
Moreover, they demonstrated that genetic restoration of CHD8 expression at a fetal stage ameliorated both the abnormal differentiation of ventral progenitor cells and the behavioral abnormalities in mice.
Future prospects
While CHD8 has attracted attention as a major autism-associated gene, it remained unclear when, where, and in which cell types it contributes to the behavioral abnormalities underlying the core symptoms of autism. The present study revealed that the neurodevelopmental differences at the root of the behavioral abnormalities stem from aberrant differentiation of ventral progenitor cells at the midfetal stage (Figure 4). The present findings are expected to significantly advance our understanding of the mechanism underlying the onset of autism and pave the way for the development of new therapeutic strategies targeting specific neurodevelopmental stages or cell types.
Glossary
*1) CHD8
Abbreviation of Chromodomain Helicase DNA binding protein 8, a protein belonging to a group known as chromatin remodelers, which utilize intracellular energy to alter chromosome structure and regulate gene expression levels.
*2) Ventral progenitor cells
Ventral progenitor cells are undifferentiated cells that can differentiate into neurons or glial cells during brain development. In particular, neural progenitor cells located in the ventral region of the brain serve as the origin of cells, such as inhibitory neurons and oligodendrocytes, which are crucial for regulating the function of neural circuits.
*3) Inhibitory neuron
Inhibitory neurons are those within neural circuits that suppress the activity of other neurons. They primarily use the neurotransmitter GABA to suppress excessive neuronal excitation and maintain a balance of information processing within the brain.
*4) Oligodendrocyte
Oligodendrocytes are a type of glial cell in the brain and spinal cord that form the myelin sheath covering the axons of neurons. The myelin sheath increases the conduction velocity of nerve signals and is essential for the proper functioning of neural circuits.
*5) In vivo analysis of neural circuit functions
An analytical method for investigating how neural circuits function by stimulating and recording from specific neurons or neural circuits in the brain of living animals. In this study, the presence or absence of abnormalities in neural circuits was evaluated by selectively stimulating specific neurons and observing the effects.
Funders
JST fellowship (JPMJSP2135), JSPS fellowship (JP21J00911), JSPS KAKENHI grants (JP25KJ0256, JP25K19075, JP21K15726, JP21H05619, JP22H05493, JP23K14795, JP22H04925, JP21H02847, JP24H00627), AMED grants (JP22gm6310008, JP24wm0625316), a grant from SECOM Science and Technology Foundation, and a research grant from Astellas Foundation for Research on Metabolic Disorders.
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Nature Communications
Defective ventral neurogenesis due to midfetal Chd8 mutation drives autistic-like behavior in mice
27-May-2026