Targeting oxytocin receptor (Oxtr)-expressing neurons in the lateral septum to restore social novelty in autism spectrum disorder mouse models

Machi Horiai,Yuichi Hiraoka,Ryoichi Teruyama,Shinji Miyazaki,Masaru Tamura,Hiroaki Mizukami,Tamio Furuse,Kenju Shimomura,Ryotaro Hayashi,Shizu Hidema,Yuko Maejima,Haruhiko Bito,Katsuhiko Nishimori,Ayano Otsuka

doi:10.1038/s41598-020-79109-0

Abstract

Autism spectrum disorder (ASD) is a continuum of neurodevelopmental disorders and needs new therapeutic approaches. Recently, oxytocin (OXT) showed potential as the first anti-ASD drug. Many reports have described the efficacy of intranasal OXT therapy to improve the core symptoms of patients with ASD; however, the underlying neurobiological mechanism remains unknown. The OXT/oxytocin receptor (OXTR) system, through the lateral septum (LS), contributes to social behavior, which is disrupted in ASD. Therefore, we selectively express hM3Dq in OXTR-expressing (OXTR+) neurons in the LS to investigate this effect in ASD mouse models developed by environmental and genetic cues. In mice that received valproic acid (environmental cue), we demonstrated successful recovery of impaired social memory with three-chamber test after OXTR+ neuron activation in the LS. Application of a similar strategy to Nl3R451C knock-in mice (genetic cue) also caused successful recovery of impaired social memory in single field test. OXTR+ neurons in the LS, which are activated by social stimuli, are projected to the CA1 region of the hippocampus. This study identified a candidate mechanism for improving core symptoms of ASD by artificial activation of DREADDs, as a simulation of OXT administration to activate OXTR+ neurons in the LS.

Highlights

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder associated with a combination of heterogeneous genetic variations; environmental cues have been suspected to be associated with ASD
Based on previous findings[22,28], we expected that the activation of oxytocin receptor (OXTR)+ neurons in the lateral septum (LS) and in the neural circuits composed of such neurons, with the administration of OXT might compensate for the impaired OXTR signalling in valproic acid (VPA) mice and ameliorate their ASD-like symptoms
An hM3Dq vector was injected into the LS of VPA mice; subsequently, the operated mice were characterized according to social novelty, anxiety, and repetitive behaviors, which are considered related to dysfunction in human ASD (Fig. 1E)

Summary

Introduction

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder associated with a combination of heterogeneous genetic variations; environmental cues have been suspected to be associated with ASD. It was shown that after early neonatal OXT manipulation, the number of OXT-expressing cells was significantly restored in the PVN of VPA rats, and there was a long-term therapeutic effect on autistic-like behavior[21] These studies strongly suggest that OXT administration has significant potential in the treatment of ASD. In a psychological study of human, Chen et al reported the close relation between human social behavior and neural activation after intranasal administration of OXT, in lateral septal nucleus, where the level of Oxtr gene expression was suspected to be affected by its DNA methylation level[23]. There’s no literature with description that the OXTR expressed in lateral septal nucleus in human brain closely relates to the therapeutic mechanism by OXT, intranasally administrated to ASD patients

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