About 1 percent of people with autism are missing a gene called SHANK3, which is critical for brain development. Without this gene, individuals develop many behaviors typically associated with the disorder. In a study of mice, MIT researchers led by brain and cognitive sciences professor Guoping Feng have now shown that they can reverse some of those behavioral symptoms by turning the gene back on later in life, allowing the brain to rewire itself.
The Shank3 protein, found in synapses, helps organize the hundreds of other proteins that are necessary to coördinate a neuron’s response to incoming signals. Feng previously found that a missing or defective SHANK3 gene in mice leads to synaptic disruptions that can produce symptoms including compulsive behavior, avoidance of social interaction, and anxiety. He also showed that some synapses in these mice, especially in a part of the brain called the striatum, have far fewer dendritic spines—small buds on neurons’ surfaces that help transmit synaptic signals.
In the new study, published in Nature, he and colleagues genetically engineered mice so that their SHANK3 gene was turned off during embryonic development but could be turned back on by adding tamoxifen to the mice’s diet.
When the researchers turned on SHANK3 in young adult mice (two to four and a half months after birth), they were able to eliminate the mice’s repetitive behavior and their tendency to avoid social interaction. At the cellular level, the team found that the density of dendritic spines dramatically increased in the striatum of treated mice, demonstrating the structural plasticity in the adult brain.
However, the mice’s anxiety and some motor coördination symptoms persisted. Feng suspects that these behaviors are probably caused by abnormal circuits irreversibly formed during early development.
When the researchers turned on SHANK3 earlier in life, only 20 days after birth, the mice’s anxiety and motor coördination did improve. The researchers are now working on defining the critical periods for the formation of these circuits, which could help them determine the best time to try 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.”
For the small population of people with SHANK3 mutations, the findings suggest that new genome-editing techniques could in theory be used to repair the defective gene and improve the symptoms, even later in life. Feng believes that scientists may also be able to develop more general approaches that would apply to a larger population.
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