Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Kohei Kitagawa,Kensuke Matsumura,Hitoshi Hashimoto,Atsushi Kasai,Kazuki Nagayasu,Kazuhiro Takuma,Masayuki Baba,Takanobu Nakazawa,Momoka Kondo,Tomoya Takemoto,Kaoru Seiriki,Atsuko Hayata-Takano,Yukio Ago,Ryota Hashimoto

doi:10.1186/s13041-021-00769-8

Abstract

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

Highlights

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication
We found that intranasal administration of oxytocin successfully ameliorated the decreased sniffing time in POGZWT/ Q1038R mice, but it did not significantly affect the sniffing time in WT mice (Fig. 1b)
We found that the oxytocin receptor gene (OXTR) mRNA and protein expression was significantly decreased in POGZWT/Q1038R mice compared to that in WT littermates (Fig. 1c, d)

Summary

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. This study explored whether oxytocin administration improves impaired social behavior in POGZWT/Q1038R mice.

Results

Conclusion