Summary: Researchers have identified a link between the Nlgn3 (neuroligin-3) gene and oxytocin signaling in mouse models of autism spectrum disorder (ASD). A mutation in Nlgn3 disrupts oxytocin responses in neurons of the brain’s reward circuitry, which leads to reduced social interactions in mice.
Source: University of Basel
A research group at the Biozentrum, University of Basel, led by Professor Peter Scheiffele, has revealed a novel connection between a genetic change and social behavior linked to autism. Their work shows that a mutation in the neuroligin‑3 (Nlgn3) gene weakens oxytocin signaling in specific brain neurons. Published in Nature, the study also describes a pharmacological approach that restores oxytocin responsiveness and improves social behavior in affected mice.
Autism spectrum disorder affects about one percent of the population and is characterized by differences in communication, repetitive behaviors, and social interaction challenges. Many different genes contribute to autism risk; among them is Nlgn3, which encodes the synaptic adhesion molecule neuroligin‑3. How this wide range of genetic alterations leads to behavioral symptoms remains poorly understood, and bridging that gap is a major obstacle to developing targeted therapies.
Scheiffele’s team investigated how an autism-associated mutation in neuroligin‑3 affects brain function and behavior in mice. Their experiments uncovered an unexpected convergence between a genetic risk factor, disruptions in neuronal protein synthesis, and altered oxytocin signaling—three elements that together help explain how distinct molecular changes can produce similar social deficits.
Mutation affects how neurons respond
Mouse models that carry mutations associated with autism are widely used to study the biological basis of the condition. In the model studied here, loss of neuroligin‑3 impairs oxytocin signaling in dopaminergic neurons of the ventral tegmental area (the brain’s reward system). This impairment reduces the animals’ social interaction and alters their behavioral responses to social novelty.
Surprisingly, the researchers found that the absence of neuroligin‑3 changes translation homeostasis—the balance of protein synthesis—within these reward‑system neurons. Those changes in protein synthesis in turn blunt the neurons’ sensitivity to oxytocin, linking a synaptic adhesion gene directly to neuropeptide signaling that governs social behavior.
Previous hypotheses have suggested oxytocin pathways could be involved in autism, but this study provides direct evidence that a specific autism‑linked gene disrupts oxytocinergic signaling in defined neurons. “We were surprised to find that Nlgn3 mutations impair oxytocin signaling pathways. This links two important puzzle pieces in the biology of autism,” says Professor Scheiffele.
Altered oxytocin signaling is reversible
Importantly, the research demonstrates that oxytocin signaling deficits caused by Nlgn3 loss are reversible. Treatment of mutant mice with a selective, brain‑penetrant inhibitor of MAP kinase‑interacting kinases (MNK) normalized translation homeostasis in the ventral tegmental area, restored oxytocin responses in dopaminergic neurons, and rescued social novelty behavior. The same pharmacological treatment also improved behavior in a second rodent model of autism, indicating potential broader relevance across different genetic forms of the condition.
These findings point to a mechanistic pathway by which a synaptic adhesion molecule affects protein synthesis control and oxytocinergic regulation of social behavior. By identifying this convergence, the study offers a framework for how diverse genetic risk factors might lead to common disruptions in social brain circuits, and it highlights translation regulation and oxytocin signaling as actionable targets for intervention in some autism cases.
About this autism and genetics research article
Source:
University of Basel
Contacts:
Peter Scheiffele – University of Basel
Image Source:
Image credited to University of Basel.
Original Research: Closed access
“Rescue of oxytocin response and social behaviour in a mouse model of autism” by Hanna Hörnberg, Enrique Pérez‑Garci, Dietmar Schreiner, Laetitia Hatstatt‑Burklé, Fulvio Magara, Stephane Baudouin, Alex Matter, Kassoum Nacro, Eline Pecho‑Vrieseling & Peter Scheiffele. Nature. DOI: 10.1038/s41586-020-2563-7
Abstract
Rescue of oxytocin response and social behaviour in a mouse model of autism
Developing effective treatments for autism spectrum disorders is challenging because of the condition’s genetic and phenotypic heterogeneity. Hundreds of risk genes have been linked to autism, many of which fall into functional groups such as synaptic proteins, translational control, and chromatin regulators. Neurochemical modulators like oxytocin and vasopressin influence social behavior, but it has been unclear whether genetic risk factors converge on oxytocinergic signaling. This study shows that an autism‑associated mutation in Nlgn3 impairs oxytocin signaling in dopaminergic neurons and alters social novelty behavior in mice. Loss of Nlgn3 disrupts translation homeostasis in the ventral tegmental area. Treating Nlgn3‑deficient mice with a selective, brain‑penetrant inhibitor of MAP kinase‑interacting kinases restores translation balance, rescues oxytocin responsiveness, and normalizes social behavior. These results reveal a point of convergence between a genetic risk factor, translational regulation, and oxytocinergic control of social circuits, suggesting that targeting shared molecular pathways may offer a pragmatic strategy to address some social deficits across genetically diverse forms of autism.