Endogenous and exogenous oxytocin manipulation rescues social recognition memory deficits in an environmental mouse model of autism

The prevalence of autism spectrum disorder (ASD) is increasing in an epidemic-like fashion, yet no drugs are available to treat this debilitating neurodevelopmental disorder. Enhancing oxytocin (OXT) signaling may improve social functioning in ASD but has pharmacological limitations if used systemically. We, therefore, investigated the impact of a brain-penetrant melanocortin 4 receptor (MC4R) agonist that stimulates endogenous OXT release on an environmental (toxicant) ASD mouse model. C57BI/6N dams were exposed perinatally to polybrominated diphenyl ethers (PBDEs), a commercial mixture of flame retardants, DE-71 at 0.1 (L-DE-71) or 0.4 (H-DE-71) mg/kg bw/d for 10 weeks. Controls received corn oil vehicle (VEH/CON). L-DE-71 females and L-DE-71 and H-DE-71 males did not prefer novel conspecifics on a social novelty preference (SNP) test, indicating deficient short-term social recognition memory. In adult offspring, treatment with MC4R agonist, Ro21-3225 trifluoroacetate salt (7.5 and 15mg/kg ip) or intranasal OXT (iOXT, 9IU/kg) reversed the deficient SNP in FMR1KO females (p<0.05, n=4) but not L-DE-71 females. In adult males, both MC4R agonist and iOXT reversed deficient SNP in L-DE-71 and H-DE-71 mice (p<0.05-.01, n=3-5/group). To investigate the effects of intervention during the critical period of development of the OXT system, we examined outcomes of chronic developmental administration of iOXT in offspring at postnatal day (P)28-33 on long-term social recognition memory (SRM) and repetitive behavior using the marble burying (MB) test. We also examined OXT immunoreactivity in the paraventricular nucleus of the hypothalamus (PVH) and the connectivity of the OXTergic circuit from the prefrontal cortex (PFC) to the basolateral amygdala (BLA). DE-71-exposed offspring received intranasal oxytocin (iOXT; 0.1IU/kg) or saline (iSAL) at P7-21. Compared to vehicle controls, L-DE-71 female and H-DE-71 male offspring receiving iSAL showed deficient SRM (n=3-5). iOXT prevented long-term SRM deficits in DE-71-exposed females (p<0.0001, n=11) but not the exaggerated digging on MB in juvenile L-DE-71 females or males vs. vehicle controls. L-DE-71+iOXT females also displayed reduced PVH OXT immunoreactivity vs. L-DE-71+iSAL (p<0.01, n=4/group). No significant effects of iOXT were observed on PFC-BLA connectivity (n=2-4/group). Our data suggests that developmental iOXT and adult activation via MC4R agonist treatment improves social but not repetitive behaviors in a sex-dependent manner, pointing to the critical role of OXT and its therapeutic potential to improve ASD-like symptoms caused by maternal transfer to offspring of environmental pollutants such as PBDEs. Funding: This work was supported by a RISE fellowship to AGC, NIH fellowship award F31ES034304 to E.V.K., and a UCR COR grant to MCC. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.