New Insights into the Link Between Shank3 Gene Mutation and Autism

A recent study has revealed how a mutation in the Shank3 gene, associated with autism, alters social behavior by disrupting the release of vasopressin in the brain. In mice, this mutation led to reduced social communication and defensive aggression by limiting vasopressin access to the lateral septum.

A New Mechanism Unveiled

A team of researchers at the Laboratory of Cognition and Social Interactions at the Spanish Institute of Neuroscience, led by Felix Leroy, conducted a pioneering study aimed at unraveling the connection between the Shank3 gene mutation and changes in social behavior. The researchers used a mouse model carrying this autism-related mutation to demonstrate that the hormone vasopressin, essential for social relationships, is not properly secreted in the lateral septum of the brain.

The findings were published in the journal Nature Communications, where the study showed that proper vasopressin secretion in this region regulates social behaviors through two different receptor pathways: one controlling social communication and the other managing social aggression. The researchers were able to reverse the social interaction deficits without causing unwanted aggressive responses by selectively activating these receptors.

Biological Mechanism Details

This study provides the first detailed explanation of how a genetic mutation is linked to autism and social interaction problems. Until now, the Shank3 gene was associated with the disorder, but the biological mechanism explaining this relationship was unclear. The key, as this study shows, lies in vasopressin, a brain hormone acting as a messenger between neurons, crucial for regulating social communication and aggression in male mice.

The researchers observed that animals with the mutation lost some of the vasopressin-producing neurons in the bed nucleus of the stria terminalis. They confirmed that these neurons release vasopressin into the lateral septum, explaining the reduced amount of vasopressin reaching the lateral septum.

New Therapeutic Possibilities

These findings open the door to potential personalized treatments for autism. The study showed that vasopressin operates in the lateral septum via two different receptors, each responsible for a specific aspect of behavior: the AVPR1a receptor controls social communication, while the AVPR1b receptor regulates social aggression. By manipulating these receptors, researchers were able to restore each behavior independently.

“We managed to improve social communication without increasing aggression, which is crucial if we are considering future treatments,” Leroy explains. To achieve this, the team used a new vasopressin sensor developed in collaboration with Yulong Li’s lab at Peking University, allowing them to observe how vasopressin is secreted in the brain in real-time.

Conclusion

This groundbreaking study illustrates how a mutation in the Shank3 gene can lead to significant changes in social behavior by affecting vasopressin secretion in the brain. By understanding how vasopressin functions through specific receptors, new treatments can be developed to enhance social interaction in individuals with autism without causing unwanted side effects like aggression. This discovery opens the door to personalized therapies that consider sexual and genetic differences.