Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism

Hara, Yuta; Ago, Yukio; Higuchi, Momoko; Hasebe, Shigeru; Nakazawa, Takahiro; Hashimoto, Hitoshi; Matsuda, Takehisa; Takuma, Kazuhiro

doi:10.1016/j.yhbeh.2017.09.013

Cited by 55 publications

(49 citation statements)

References 51 publications

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“…Similar to the findings of a recent study ( Hara et al, 2017 ), we also observed that a single intranasal OXT could restore the social preference deficits of VPA rats. The pro-social effects of nasal OXT manipulation have been confirmed in animal studies ( Bales et al, 2014 ; Calcagnoli et al, 2015 ; Simpson et al, 2017 ) and clinical studies ( Hollander et al, 2003 ; Andari et al, 2010 ; Watanabe et al, 2015 ; Yatawara et al, 2016 ).…”

Section: Discussionsupporting

confidence: 91%

“…The pro-social effects of nasal OXT manipulation have been confirmed in animal studies ( Bales et al, 2014 ; Calcagnoli et al, 2015 ; Simpson et al, 2017 ) and clinical studies ( Hollander et al, 2003 ; Andari et al, 2010 ; Watanabe et al, 2015 ; Yatawara et al, 2016 ). Although the underlying mechanism is unclear, immunohistochemical staining of c-Fos ( Jia et al, 2008 ; Hara et al, 2017 ) and imaging studies ( Bethlehem et al, 2013 ; Rilling et al, 2014 ) have shown that nasal administration of OXT activates social behavior-relevant areas in the brain. However, an acute exogenous OXT supplementation only produced a temporary pro-social effect ( Penagarikano et al, 2015 ; Hara et al, 2017 ), probably because the half-life of OXT in the brain is relatively short ( Jones and Robinson, 1982 ; Mens et al, 1983 ).…”

Section: Discussionmentioning

confidence: 99%

“…Offspring in these cases have been reported to exhibit a series of autistic behaviors, including reduced ultrasonic communication, impaired social interaction, and repetitive/stereotyped behaviors ( Roullet et al, 2013 ; Nicolini and Fahnestock, 2018 ). Importantly, this autistic model has been widely used to investigate the intrinsic link between some environmental risk factors and the pathogenesis of ASD ( Stefanik et al, 2015 ; Bertelsen et al, 2017 ; Hara et al, 2017 ; Wu et al, 2017 ; Yamaguchi et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism

Dai

Zhang

Schön

et al. 2018

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) is characterized by impaired social communication and repetitive/stereotyped behaviors. The neuropeptide oxytocin (OXT) plays a critical role in regulating social behaviors in the central nervous system, as indicated in both human and animal studies. We hypothesized that central OXT deficit is one of causes of etiology of ASD, which may be responsible for the social impairments. To test our hypothesis, central OXT system was examined in valproic acid (VPA)-induced rat model of autism (VPA rat). Our results showed that adolescent VPA rats exhibited a lower level of OXT mRNA and fewer OXT-ir cells in the hypothalamus than control rats. Additionally, OXT concentration in cerebrospinal fluid (CSF) was reduced. The number of OXT-ir cells in the supraoptic nucleus (SON) of neonatal VPA rats was also lower. Autistic-like behaviors were observed in these animals as well. We found that an acute intranasal administration of exogenous OXT restored the social preference of adolescent VPA rats. Additionally, early postnatal OXT treatment had long-term effects ameliorating the social impairments and repetitive behaviors of VPA rats until adolescence. This was accompanied by an increase in OXT-ir cells. Taken together, we demonstrated there was central OXT deficiency in the VPA-induced rat model of autism, and showed evidence that early postnatal OXT treatment had a long-term therapeutic effect on the autistic-like behaviors in VPA rats.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism

Dai

Zhang

Schön

et al. 2018

Front. Cell. Neurosci.

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“…Hara et al 20 reported that administration of intranasal oxytocin attenuates the social deficits of adult VPA mice. Therefore, we considered whether oxytocinergic signalling was altered in VPA pups.…”

Section: Resultsmentioning

confidence: 99%

Oxytocin ameliorates maternal separation‐induced ultrasonic vocalisation calls in mouse pups prenatally exposed to valproic acid

Tsuji

Fujisaku

Tsuji

2020

J Neuroendocrinology

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Autism spectrum disorder (ASD) is a neurodevelopmental disorder estimated by the World Health Organization to occur in one of 160 children worldwide. No pharmaceutical treatments are available to improve the deficits in social communication that are common symptoms of ASD. Recent clinical trials have focused on the nasal application of oxytocin, a neuronal peptide known to regulate a variety of social behaviours. However, the effect of oxytocin on this deficit is inconclusive. By contrast, evidence from ASD animal model studies indicates that when animals are treated with oxytocin during early development, improvements in social deficits are observed in adulthood. Thus, it is necessary to examine the effect of therapeutic target medication prescribed in early development. Mice prenatally exposed to valproic acid (VPA) are widely used as an animal model of ASD. However, many behavioural studies have been conducted during adulthood rather than early development. To establish a screening system to identify therapeutic drugs that are effective when delivered during the early postnatal period, it is important to examine the early developmental changes in their communicative behaviours. In the present study, we examined the ultrasonic vocalisation (USV) of VPA-exposed mice pups during their early postnatal developmental days. USV rates were comparable to those of the controls until the first week of their life but declined more on postnatal day 11. We checked the expression of oxytocin system in the hypothalamus and found the down-regulation of oxytocin and CD38, and up-regulation of oxytocin receptor in the VPA pups. Acute administration of oxytocin on postnatal day 11 increased the call rate of VPA pups.Taken together, we have demonstrated there was a deficiency in the oxytocinergic signalling in the VPA pups and also shown the existence of time periods that are effective with respect to screening the therapeutic drugs. K E Y W O R D Sautism spectrum disorder, early neurodevelopment, oxytocin, valproic acid mouse model

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“…In the present study, we adopted the subcutaneous injection to deliver precise amount of OXT to immature mice, and observed significant effects of oxytocin on social behaviors compared with the saline. Several studies have shown that intranasal administration of oxytocin increases its concentrations in both brain tissue and plasma 31 and affects behaviors relating higher brain functions 12 . On the other hand, there also have been several reports showing that peripheral injection of oxytocin increases its concentrations in both brain tissue and plasma with a pharmacokinetic profile different from nasal delivery 31 , and induces some behavioral changes relating higher brain functions 14 , consistent with the present results.…”

Section: Discussionmentioning

confidence: 99%

Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits

Nagano

Takumi

Suzuki

2018

Sci Rep

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Disturbance of neurotransmitters and neuromodulators is thought to underlie the pathophysiology of autism spectrum disorder (ASD). Studies of 15q dup mouse models of ASD with human 15q11–13 duplication have revealed that restoring serotonin (5-HT) levels can partially reverse ASD-related symptoms in adults. However, it remains unclear how serotonin contributes to the behavioral symptoms of ASD. In contrast, oxytocin (OXT) has been found to involve social and affiliative behaviors. In this study, we examined whether serotonin-OXT interaction during the early postnatal period plays a critical role in the restoration of social abnormality in 15q dup mice. OXT or the 5-HT1A receptor agonist 8OH-DPAT treatment from postnatal day 7 (PD7) to PD21 ameliorated social abnormality in the three-chamber social interaction test in adult 15q dup mice. The effect of 8OH-DPAT was inhibited by blockade of OXT receptors in 15q dup mice. Thus, serotonin-OXT interaction via 5-HT1A receptors plays a critical role in the normal development of social behavior in 15q dup mice. Therefore, targeting serotonin-OXT interaction may provide a novel therapeutic strategy for treatment of ASD.

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Oxytocin attenuates deficits in social interaction but not recognition memory in a prenatal valproic acid-induced mouse model of autism

Cited by 55 publications

References 51 publications

Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism

Neonatal Oxytocin Treatment Ameliorates Autistic-Like Behaviors and Oxytocin Deficiency in Valproic Acid-Induced Rat Model of Autism

Oxytocin ameliorates maternal separation‐induced ultrasonic vocalisation calls in mouse pups prenatally exposed to valproic acid

Critical roles of serotonin-oxytocin interaction during the neonatal period in social behavior in 15q dup mice with autistic traits

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