Abstract
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.
Highlights
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior, interests, or activities (DSM-5)
Because a similar early intervention study found that the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) was effective[5], we examined whether early postnatal OXT treatment ameliorated the abnormal social interaction observed in adult 15q dup mice
In the open field (OF) test, the OXT treatment did not affect the total distance traveled in the OF in either wild type (WT) or 15q dup mice (Fig. 1a; two-way ANOVA; interaction: F1,43 = 0.238, p = 0.628; drug: F1,43 > 0.001, p = 0.981; genotype: F1,43 = 0.066, p = 0.798; Dunnett’s test: WT-saline, 6,650 ± 508 cm vs. WT-OXT, 6,390 ± 540 cm, p = 0.974: WT-saline vs. 15q dup-saline, 6,530 ± 351 cm, p = 0.997: WT-saline vs. 15q dup-OXT, 6,770 ± 488 cm, p = 0.996)
Summary
Autism spectrum disorder (ASD) is a neurodevelopmental disorder defined by deficits in social communication and interaction, as well as restricted and repetitive patterns of behavior, interests, or activities (DSM-5). 15q dup mice exhibit low serotonin levels in the brain during development[4] These mice show reversibility of a subset of ASD-related symptoms in adults by the restoration of normal serotonin levels during postnatal development[5]. OXT is released in the brain and acts as a hormone or neuromodulator on a variety of neurotransmitter systems including GABA19,20, dopamine[21] and serotonin[22,23,24,25,26] Among these mechanisms, the interaction between OXT and serotonin is of particular interest, because both molecules are involved in the control of social behavior[27,28]. In the current study, we examined whether the OXT system is involved in the effects of serotonergic intervention in 15 dup mice during the early postnatal period
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