Mouse study links vasopressin pathway to social deficits tied to autism, suggests target for drugs

Researchers in Spain report that a mutation in a gene long associated with neurodevelopmental disorders disrupts release of the hormone vasopressin in mice, producing social deficits that resemble core features of autism spectrum disorder and pointing to a receptor pathway that could be targeted by future therapies.

In a study published in Nature Communications in July, investigators at the Institute of Neurosciences at Universidad Miguel Hernández de Elche genetically engineered mice to carry a mutation in the Shank3 gene. Mice with the Shank3 mutation showed reduced exploratory and social behaviors compared with control animals, and the researchers traced those changes to a deficit in vasopressin-producing neurons that normally project to the lateral septum, a brain region implicated in social behavior, anxiety and fear.

The team, led by Dr. Félix Leroy, reported that Shank3-mutant mice had fewer neurons that release vasopressin and lower vasopressin levels in the lateral septum. Vasopressin binds to multiple receptors and can influence both the interpretation of social cues and aggressive behaviors. By experimentally manipulating these receptor pathways separately, the researchers were able to restore measures of sociability in the mutant mice without producing excessive aggression.

"We managed to improve sociability without increasing aggression, which is fundamental if we are thinking about a future treatment," Dr. Leroy said in a statement accompanying the paper. The group has filed a patent application aimed at developing drugs that selectively activate the AVPR1a receptor, which the authors identify as controlling sociability, as a potential route to reduce social deficits without triggering aggression.

The study used a series of behavioral assays, including free-roaming tests, one-on-one social interactions and the introduction of an unfamiliar mouse to the animals' environment. Mutant mice explored less and engaged less with other mice than controls. The authors interpret the behavior as evidence that impaired vasopressin signaling from the hypothalamus to the lateral septum contributes to social impairment in this genetic model.

The findings add a mechanistic layer to prior work linking Shank3 mutations to neurodevelopmental conditions. Shank3 encodes a synaptic scaffolding protein important for the structure and function of neuronal connections. Mutations in Shank3 have been associated in previous studies with autism and other neurocognitive disorders, but the pathways by which such mutations alter social behavior have been unclear.

The authors also note sex-related differences in the vasopressin pathway that could help explain the higher diagnosed prevalence of autism in males. In U.S. Centers for Disease Control and Prevention data cited by the researchers, roughly one in 31 children are identified with autism today compared with about one in 150 in the early 2000s, and boys are diagnosed at higher rates than girls. The paper cautions, however, that how findings in mice translate to humans remains uncertain.

Genetic factors are known to account for a substantial portion of autism risk; estimates cited in the study and associated materials range from about 40 percent to 80 percent, and some single-gene mutations are estimated to underlie a minority of cases. The authors write that targeting downstream neurochemical pathways affected by genetic mutations could offer a complementary strategy to approaches that focus directly on genes.

Current drugs that modify vasopressin signaling, such as tolvaptan and conivaptan, are approved for conditions involving water balance and low sodium levels rather than social behavior. The researchers say their approach would aim for receptor selectivity to avoid the physiological effects those drugs produce and to limit behavioral side effects such as increased aggression.

Independent experts cautioned that rodent findings require careful validation before being translated to human treatments. The Shank3 mutation mouse is one model among many used to study the biology of social behavior, and human autism is clinically and genetically heterogeneous. The authors acknowledge those limitations and call for further preclinical work to assess safety, efficacy and sex-specific effects before any clinical testing.

The study provides a defined neurochemical mechanism linking a well-studied genetic risk factor to altered social circuits in the brain and identifies a receptor-based strategy that the authors say could be explored as a therapeutic avenue. Translational steps would include confirming the pathway's relevance in human tissue or clinical populations and developing drugs that engage the AVPR1a receptor with the needed specificity and safety profile.