Autism – a complex developmental disorder involving persistent deficits in social communication and interaction and repetitive behaviors – is known to have a strong genetic basis, although the genetics of autism are complex and it is unclear whether autism spectrum disorder (ASD) is caused by multiple genes or by rare mutations. The condition affects one in 50 children and four times as many boys as girls.  

The effect of genetic mutations on the development of autism

In recent years, there has been substantial research displaying the effect of genetic mutations on the development of autism and other neurodevelopmental disorders.  Based on those studies, researchers have focused attention on similarities behind those mutations and how they affect the functioning of the brain. A study conducted by Prof. Sagiv Shifman from the Life Sciences Institute and the Autism Center at the Hebrew University of Jerusalem has found in work on mice that genes connected 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.  

The cerebellum, a major structure of the hindbrain that is located near the brainstem, is responsible for coordinating voluntary movements and a number of other functions including motor skills such as balance, coordination, and posture. Recent studies have shown that his brain region also contributes to the development of many social and cognitive functions.  Based on these discoveries, the Hebrew University research team is hopeful this can lead to a better understanding of the connection between the cerebellum and autism and even lead to new therapies in the future.

One of the most prominent genes associated with autism

The Hebrew University study entitled “Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice” has just been published in the prestigious journal Nature Communications. The team tested one of the most prominent genes associated with autism –called Pogz.  They chose this specific gene based on prior findings that links it to developmental disorders and overly friendly behavior in some patients on the autism spectrum. 

Several genes implicated ASD are chromatin regulators, a DNA scaffold that can respond to external cues to regulate the many uses of DNA. Chromatin is the material that makes up a chromosome consisting of DNA and protein, and it is important because it uses a “packing trick” to get all the DNA inside a cell, including POGZ.

Brain development in mice and specifically

In partnership with Prof. Yosef Yarom from the university’s Safra and other labs around the world, the research team investigated how a mutation in the Pogz gene impacted on brain development in mice and specifically on the functioning of the cerebellum. The team showed that that mutations in Pogz result in behavioral deficits and growth impairments that resemble the condition in humans.

The findings concluded that the mutation led to hyper-social behavior and learning disabilities while also affecting on the physical development of the mice. Upon further investigation, the research team also observed that the genetic mutation affected the proliferation of cells in the brain and inhibited the production of new nerve cells. The researchers believe that this may be a reason why some children with the mutation exhibit smaller-than-average head sizes.  

Drugs that would directly change the neural processes

While there are presently no effective medicines for the main symptoms of autism, Yarom believes that their research could lead to the development of drugs that would directly change the neural processes in the cerebellum. Previous research that he has led showed that specific chemical agents that could change the active functioning of the cerebellum. Ongoing research will therefore be focused on whether similar approaches could lead the lab mice to change their behavior and reverse the effects connected with the mutation.

“Our work with this specific gene that we know is connected to autism and significantly impacts on the functioning of the brain provide us with considerable hope that we will be able to develop medicines to assist children with autism,” Shifman and Yarom concluded. “Enhanced understanding of the neurological processes behind autism opens up hope-filled possibilities for new treatments.”