Shank3 ranks among the best studied genes associated with autism. Around 1 percent of people with autism lack a working copy of the gene, which is critical for brain development.
Now researchers working with genetically engineered mice have shown that they can reverse repetitive behaviors and social avoidance by switching a disabled SHANK3 gene back on – even in adulthood. The result, they say, hints that the mature brain can at least partially rewire itself.
“In thinking about the development of new therapies for autism, there has long been a question of whether these potential therapies would have much benefit in older individuals,” comments Mathew Pletcher, Autism Speaks vice president, head of genomic discovery. “This study provides further evidence that even in adulthood, changes that address the underlying genetic cause of autism could provide a benefit.”
“This suggests that, even in the adult brain, we have profound plasticity to some degree,” says senior study author Guoping Feng, a neuroscientist at the Massachusetts Institute of Technology (MIT). “There is more and more evidence showing that some of the defects are indeed reversible.”
Vital for brain communication
The Shank3 gene spells out instructions for creating a protein that helps brain nerve cells (neurons) communicate with each other. The Shank3 protein also helps organize hundreds of other proteins involved in coordinating a neuron’s response to incoming signals.
A missing or defective Shank3 gene disrupts communication between neurons and is associated with repetitive behaviors, avoidance of social interaction, anxiety and difficulty with motor coordination.
In previous research, the MIT investigators showed that Shank3 gene defects also reduce the abundance of dendritic spines – small buds on the neurons’ surface that help convey signals between brain cells – in some brain areas. (See photo above.)
Engineering an off/on gene switch
In the new study, the MIT researchers genetically engineered mice to turn off so that their Shank3 gene was turned off during embryonic development but could be turned back on by adding the drug tamoxifen to the mice’s diet. (To be clear, the researchers are not proposing to use tamoxifen as a treatment for autism. Rather, they cleverly engineered their gene knock-out to be reversed by the chemical.)
When the researchers switched on the gene in young adult mice (1 to 4.5 months old), the mice lost their social avoidance and stopped engaging in repetitive behaviors such as compulsive grooming.
Inside the brain, the team found that the density of neuron dendritic spines dramatically increased in brain areas where they had been abnormally reduced. This, they said, demonstrates the adult brain’s plasticity, or ability to “rewire.”
However, the mice’s anxiety and motor coordination symptoms did not disappear. The researchers speculated that these behaviors were tied to early brain connections that are not easily reversed during adulthood.
To test this idea, the researchers tried switching on the Shank3 gene just 20 days after birth. In response, the mice’s anxiety and motor coordination improved.
The research team is now working on identifying the critical periods for the formation of Shank3-controlled brain connections. This, they hope, will help them determine the best time to intervene.
“Some circuits are more plastic than others,” Feng says. “Once we understand which circuits control each behavior and understand what exactly changed at the structural level, we can study what leads to these permanent defects, and how we can prevent them from happening.”
Relevance to people?
How might these findings in genetically engineered mice apply to the 1 percent of people with autism and Shank3 mutations?
In theory, the study authors say, the findings suggest that new gene-editing techniques could someday be used to repair defective Shank3 genes and, so, ease autism symptoms, even in adulthood. However, such techniques are not yet ready for use in humans.
In addition, Feng says that the insights from their study may guide more general approaches to repair or support brain connections to ease some of autism’s most disabling symptoms.