Fetal exposure to valproic acid dysregulates the expression of autism-linked genes in the developing cerebellum

Autism spectrum disorder (ASD) includes a set of highly heritable neurodevelopmental syndromes characterized by social and communication impairment, repetitive behaviour, and intellectual disability. Although mutations in multiple genes have been associated to ASD, most patients lack detectable genetic alterations. For this reason, environmental factors are commonly thought to also contribute to ASD aetiology. Transcriptome analyses have revealed that autistic brains possess distinct gene expression signatures, whose elucidation can provide insights about the mechanisms underlying the effects of ASD-causing genetic and environmental factors. Herein, we have identified a coordinated and temporally regulated programme of gene expression in the post-natal development of cerebellum, a brain area whose defects are strongly associated with ASD. Notably, this cerebellar developmental programme is significantly enriched in ASD-linked genes. Clustering analyses highlighted six different patterns of gene expression modulated during cerebellar development, with most of them being enriched in functional processes that are frequently dysregulated in ASD. By using the valproic acid mouse model of ASD, we found that ASD-linked genes are dysregulated in the developing cerebellum of ASD-like mice, a defect that correlates with impaired social behaviour and altered cerebellar cortical morphology. Moreover, changes in transcript levels were reflected in aberrant protein expression, indicating the functional relevance of these alterations. Thus, our work uncovers a complex ASD-related transcriptional programme regulated during cerebellar development and highlight genes whose expression is dysregulated in this brain area of an ASD mouse model.

Automated summary

Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental syndrome characterized by social and communication impairment, repetitive behavior, and intellectual disability. Despite the association of multiple genes with ASD, most patients do not have detectable genetic alterations, suggesting the involvement of environmental factors. Transcriptome analysis reveals distinct gene expression patterns in autistic brains, providing insight into the mechanisms underlying the effects of genetic and environmental factors. A study focusing on the cerebellum, a brain area strongly associated with ASD, identifies a coordinated and temporally regulated gene expression program during postnatal development, enriched in ASD-linked genes. Dysregulation of these genes in the developing cerebellum of an ASD mouse model correlates with impaired social behavior and altered cerebellar morphology. The findings highlight the importance of understanding the complex transcriptional program related to ASD in cerebellar development and the dysregulation of genes in this brain area.