How a Genetic Mutation Linked to Autism Affects Vasopressin Production and Social Behaviors

Researchers have uncovered a key biological mechanism connecting a mutation in the Shank3 gene, associated with autism, to changes in social behavior. Utilizing a mouse model carrying this specific mutation, the study demonstrates that vasopressin, a critical hormone in the brain responsible for social bonding and territorial behaviors, isn't properly released in the brain's lateral septum area.

This research was conducted by the Cognition and Social Interactions laboratory, led by Félix Leroy at the Institute for Neurosciences, a joint venture of the Spanish National Research Council (CSIC) and the Miguel Hernández University of Elche. The findings, published in Nature Communications, show that correct vasopressin release in this brain region influences social behaviors through two receptor pathways: AVPR1a, which governs sociability, and AVPR1b, which manages social aggression.

In the mutant mice, part of the vasopressin-releasing neuron population in the bed nucleus of the stria terminalis (BNST) was diminished, leading to reduced vasopressin reaching the lateral septum. This disruption explains the observed decrease in social interactions and territorial defense responses, behaviors usually crucial for male mice.

The study highlights that vasopressin operates via these two distinct receptors, and manipulating their activity can independently restore social or aggressive behaviors. For instance, activating AVPR1a improves sociability without increasing aggression, suggesting potential targeted therapies for social deficits.

A novel vasopressin biosensor, developed in collaboration with Yulong Li's lab at Peking University, allowed real-time visualization of vasopressin release in the brain, revealing that the mutation's effects are localized to specific neural circuits.

Importantly, the research has led to a patent application aiming to develop drugs that selectively activate the AVPR1a receptor, with the goal of improving social functioning in individuals with autism in a side effect-free manner.

The experiments focused on male mice, as vasopressin pathways are more prominent in males, contributing to territorial and aggressive behaviors. This sex difference could partly explain why autism is more commonly diagnosed in males, although further sex-specific studies are necessary.

Overall, this research provides critical insights into the biological underpinnings of autism-related social deficits and points toward personalized, circuit-specific therapeutic strategies targeting vasopressin receptors.