For people diagnosed with one of the many disorders associated with autism, connecting with others socially ranges anywhere from being somewhat difficult to near impossible.
Now researchers have traced the region in the brain where a faulty gene becomes a faulty neural pathway to explain how a certain form of this condition develops, and the discovery could lead to more effective and personalised treatment in the future.
Scientists at Beth Israel Deaconess Medical Centre in Boston, Massachusetts, turned their focus to a set of genes known to be linked with autism, and discovered how it affected specific pathways in the brain – and also how to turn its affect off in mice.
Autism isn’t a single condition, but rather describes a spectrum of behaviours and characteristics related to how a person senses and interacts with their environment.
As such, it’s typically given the banner term autism spectrum disorder (ASD), and can include individuals who have extreme difficulty interacting socially and struggle to communicate verbally and non-verbally.
The behaviours are often noticed in children – mostly boys – around the ages of 2 or 3, and can include heightened sensitivity to everyday sounds or sensations, intense focus on a particular subject, and repetitive body movements such as hand flapping or pacing.
While the conditions vary in prevalence across the globe, a study conducted in 2012 estimated on average ASD affected 62 out of 10,000 individuals.
One of those genes could be UBE3A, which when accidentally copied a few too many times can give rise to isodicentric chromosome 15 syndrome – a chromosomal disorder that researchers have recently linked with ASD.
On the other hand, those who don’t have the gene develop a condition called Angelman syndrome, which causes developmental disabilities, jerky hand movements, seizures, and increased sociability.
“In this study, we wanted to determine where in the brain this social behaviour deficit arises and where and how increases of the UBE3A gene repress it,” said researcher Matthew Anderson.
In previous research, Anderson and his team engineered mice with extra copies of the UBE3A gene, which resulted in impaired social interactions, reduced squeaking, and an increase in repetitive behaviours such as grooming.
Now, looking more closely at how the genes behaved inside their cells, the scientists discovered that UBE3A interacts with 598 other genes.
They then turned their attention to other genes previously associated with ASD, and mapped the interactions between them and UBE3A.
When the researchers deleted one of the cerebellin genes – called CBLN1 – inside neurons with a certain type of synapse, they recreated the same characteristics seen in mice with too much UBE3A.
“When we deleted the gene and were able to reconstitute the social deficits, that was the moment we realised we’d hit the right target. Cerebellin 1 was the gene repressed by UBE3A that seemed to mediate its effects,” said Anderson.
Further experiments supported the hypothesis that seizures in those with ASD, especially in those with isodicentric chromosome 15 syndrome, were directly responsible for impairing sociability.
The team found that deleting UBE3A didn’t stop the seizures, but it did remove the consequence of social impairment.
In other words, having a little extra UBE3A – as some people with ASD have – can result in severe loss of socialising behaviours following mild seizures.
Lastly, the researchers mapped the location in the brain where UBE3A was being affected by the seizures, finding it in a rather odd location.
“Most scientists would have thought they take place in the cortex – the area of the brain where sensory processing and motor commands take place – but, in fact, these interactions take place in the brain stem, in the reward system,” said Anderson.
The exact spot is a group of neurons in the midbrain called the ventral tegmental area, which is known to play a key role in motivation, falling in love, and addiction.
Importantly, using engineered receptors that they could plant into the nerves, they found it was possible to switch the nerves on and off, increasing sociability.
We should be clear that the method was restricted to specially engineered lab mice, and inserting neural switches into humans isn’t currently a medical possibility.
But the finding does provide a target to study for other potential forms of treatment.
“It has a therapeutic flavour; someday, we might be able to translate this into a treatment that will helps patients,” said Anderson.
It might not help every individual on the spectrum, but understanding how our brain gives rise to the variety of characteristics making up ASD could bit by bit provide options for those who find socialising difficult.
This research was published in Nature.