Studying rare cases of defective Shank3 can help scientists gain insight into the neurobiological mechanisms of autism. Missing or defective Shank3 leads to synaptic disruptions that can produce autism-like symptoms in mice, including compulsive behavior, avoidance of social interaction, and anxiety, Feng has previously found. He has also shown that some synapses in these mice, especially in a part of the brain called the striatum, have a greatly reduced density of dendritic spines—small buds on neurons' surfaces that help with the transmission of synaptic signals.
In the new study, Feng 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 coordination symptoms did not disappear. Feng suspects that these behaviors probably rely on circuits that were 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 coordination 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."
Gordon Fishell, a professor of neuroscience at New York University School of Medicine, praises the study's "elegant approach" and says it represents a major advance in understanding the circuitry and cellular physiology that underlie autism. "The combination of behavior, circuits, physiology, and genetics is state-of-the art," says Fishell, who was not involved in the research. "Moreover, Dr. Feng's demonstration that restoration of Shank3 function reverses autism symptoms in adult mice suggests that gene therapy may ultimately prove an effective therapy for this disease."