Summary: A new study uncovers how a mutation in the Shank3 gene, linked to autism spectrum disorder, alters social behavior by disrupting vasopressin signaling in a specific brain circuit. In male mice carrying this autism-associated mutation, impaired vasopressin release into the lateral septum reduced sociability and diminished territorial defensive aggression.
Researchers established that vasopressin influences social behavior through two separate receptors in the lateral septum: AVPR1a mediates sociability, while AVPR1b modulates social aggression. By selectively targeting AVPR1a they were able to restore social interaction in the mouse model without provoking unwanted increases in aggression, highlighting a promising pathway for more tailored autism therapies.
Key Facts:
- Mechanism Identified: A Shank3 mutation reduces vasopressin release into the lateral septum, leading to deficits in sociability and altered aggressive responses.
- Receptor Pathways: AVPR1a in the lateral septum regulates sociability, while AVPR1b governs aspects of social aggression.
- Therapeutic Potential: Selective activation of AVPR1a improved social behavior in mice without increasing aggression, suggesting a route for focused treatments.
Source: UMH
The Cognition and Social Interactions laboratory, led by Félix Leroy at the Institute for Neurosciences — a joint center of the Spanish National Research Council (CSIC) and Miguel Hernández University (UMH) of Elche — has identified for the first time a mechanistic link between a mutation in the Shank3 gene and changes in social behavior.
Using a mouse model that carries this autism-associated Shank3 mutation, the team found that the neuropeptide vasopressin, which plays a central role in social communication and bonding, is not released normally into the lateral septum (LS). This local deficit in vasopressin signaling alters distinct aspects of social behavior.
Published in Nature Communications, the study shows that proper vasopressin release in the lateral septum controls social behavior through two distinct receptor pathways: AVPR1a supports sociability while AVPR1b controls social aggression. Importantly, selectively activating these receptor pathways can reverse the corresponding behavioral deficits without triggering other unwanted social responses.
Until now, Shank3 mutations were strongly associated with autism, but the biological mechanism connecting this gene to social deficits was not well understood. This research provides the first detailed account that links a genetic alteration in Shank3 to disrupted vasopressin neuromodulation within a specific brain circuit and to resulting behavioral changes.
The researchers observed that male mice with the mutation lost a subset of vasopressin-expressing neurons in the bed nucleus of the stria terminalis (BNST). They confirmed these BNST neurons normally send vasopressin-releasing projections to the lateral septum. Because fewer vasopressin signals reached the LS in mutant animals, those animals exhibited both reduced interest in social interaction and a pronounced loss of defensive territorial aggression, a typical male behavior for defending space.
Detailed pharmacological and circuit manipulations showed that vasopressin acts in the lateral septum through two separate receptors with distinct behavioral roles. Blocking AVPR1a in the LS impaired sociability, whereas blocking AVPR1b selectively disrupted social aggression. Conversely, selectively activating AVPR1a or AVPR1b restored sociability or aggression, respectively, in Shank3B+/- male mice.
“We managed to improve sociability without increasing aggression, which is essential if we are considering a future treatment,” explains Leroy. This receptor-specific separation of effects supports the possibility of developing targeted therapies that enhance social engagement while avoiding side effects related to aggressive behavior.
To visualize vasopressin release in real time, the team used a novel vasopressin biosensor developed in collaboration with Yulong Li’s laboratory at Peking University. This biosensor, applied for the first time to vasopressin, allowed the researchers to observe hormone release dynamics and to demonstrate that the deficit was localized to a precise circuit rather than being widespread throughout the nervous system. Computational analysis in collaboration with researchers at the University of Zurich corroborated the experimental findings.
The study’s findings are covered by a patent application aimed at developing drugs capable of selectively activating the AVPR1a receptor, with the goal of improving social deficits in people with autism while minimizing risks of increased aggression. The experiments were conducted in male mice because the vasopressin pathway is more prominent in males and only males display the form of territorial aggression under investigation.
This sex-specific pathway might partly explain why autism is more frequently diagnosed in males, although it is also possible that autism presents differently or is underdiagnosed in females. “Our results suggest future treatments could be personalized to account for these biological differences,” Leroy adds.
Funding: This research was supported by the European Research Council (ERC) under the Horizon 2020 program, the Generalitat Valenciana’s CIDEGENT fellowship, the Severo Ochoa Foundation, and the “la Caixa” Foundation, with additional grants from the U.S. National Institutes of Health (NIH), the National Natural Science Foundation of China, and the Swiss National Science Foundation.
The work is part of the MotivatedBehaviors project (H2020-ERC-STG/0784, n°949652), which investigates the lateral septum’s role in motivated behaviors to identify circuit-level changes underlying social behavior disorders. Leroy’s group has developed extensive expertise in the lateral septum, including prior work published in Cell showing how corticotropin-releasing hormone signaling from the prefrontal cortex to the lateral septum suppresses interactions with familiar individuals.
Leroy’s research trajectory has established him as a leading figure in this field, a reputation recently recognized with the EBBS Mid Career Award from the European Brain and Behaviour Society.
About this autism and genetics research news
Author: Angeles Gallar
Source: UMH
Contact: Angeles Gallar – UMH
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Impaired vasopressin neuromodulation of the lateral septum leads to social behavior deficits in Shank3B+/- male mice” by Félix Leroy et al. Nature Communications
Abstract
Impaired vasopressin neuromodulation of the lateral septum leads to social behavior deficits in Shank3B+/- male mice
The neuropeptide arginine-vasopressin (AVP) has been repeatedly linked to autism spectrum disorder (ASD), but the mechanisms by which AVP contributes to social behavior deficits were not fully clear. Using Shank3B+/- male mice as a model of ASD, which display reduced sociability and altered social aggression, the study focused on the lateral septum (LS), a brain region integral to motivated behaviors, and identified reduced AVP inputs from the bed nucleus of the stria terminalis (BNST) to the LS.
Manipulating AVP release from BNST to LS in wild-type male mice showed that AVP promotes both sociability and social aggression. Pharmacological blockade of AVPR1a in the LS impaired sociability, while blockade of AVPR1b disrupted social aggression. Selective activation of AVPR1a or AVPR1b rescued the corresponding behavioral deficits in Shank3B+/- male mice. These findings demonstrate that AVP release in the lateral septum modulates two distinct social behaviors via separate receptors and suggest a targeted strategy to restore sociability in ASD.