Recent years have provided substantial research on the effect of genetic mutations on the development of autism spectrum disorder (ASD) and other neurodevelopmental disorders.  It was found that genes associated with autism tend to be involved in the regulation of other genes and to operate preferentially in three areas of the brain; the cortex, the striatum, and the cerebellum.

In this study, we generated a mouse model with a brain-specific knockout of Pogz – a high-confidence gene for ASD. We demonstrate that Pogz deficient mice show behavioral deficits similar to the human symptoms. We found that POGZ is a negative regulator of transcription, which results in significant upregulation of gene expression, most notably in the cerebellum. Gene analysis revealed that the transcriptional changes encompass genes and pathways disrupted in ASD, including neurogenesis and synaptic processes. We also found a significant reduction in electrical activity in the cerebellar cortex, a brain region that has been consistently linked with ASD. Furthermore, this reduction reflects an increase in the inhibitory synaptic input, suggesting modification in synaptic connectivity.

Our findings support a mechanism linking gene regulation to cerebellar circuit dysfunction and behavioral abnormalities in ASD.