Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism.

Elena Minakova,Jordan Lang,Jesus-Servando Medel-Matus,Raman Sankar,Ashley Reynolds,Georgianna G Gould,Andrey Mazarati,Don Shin,Kenji Hashimoto

doi:10.1371/journal.pone.0210389

Abstract

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and repetitive behavior patterns. In humans affected by ASD, there is a male pre-disposition towards the condition with a male to female ratio of 4:1. In part due to the complex etiology of ASD including genetic and environmental interplay, there are currently no available medical therapies to improve the social deficits of ASD. Studies in rodent models and humans have shown promising therapeutic effects of oxytocin in modulating social adaptation. One pharmacological approach to stimulating oxytocinergic activity is the melanocortin receptor 4 agonist Melanotan-II (MT-II). Notably the effects of oxytocin on environmental rodent autism models has not been investigated to date. We used a maternal immune activation (MIA) mouse model of autism to assess the therapeutic potential of MT-II on autism-like features in adult male mice. The male MIA mice exhibited autism-like features including impaired social behavioral metrics, diminished vocal communication, and increased repetitive behaviors. Continuous administration of MT-II to male MIA mice over a seven-day course resulted in rescue of social behavioral metrics. Normal background C57 male mice treated with MT-II showed no significant alteration in social behavioral metrics. Additionally, there was no change in anxiety-like or repetitive behaviors following MT-II treatment of normal C57 mice, though there was significant weight loss following subacute treatment. These data demonstrate MT-II as an effective agent for improving autism-like behavioral deficits in the adult male MIA mouse model of autism.

Highlights

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and stereotypical behavior patterns often involving repetitive activities [1]
We noted a significant increase of oxytocin receptor expression in the anterior cingulate cortex in the maternal immune activation (MIA) mice, which is a region of the brain with a key role in socio-emotional processing
Current epidemiological evidence suggests that maternal immune activation (MIA) secondary to infection during pregnancy may be an environmental risk factor predisposing towards the development of ASD [3, 34, 35, 36, 37, 38]

Summary

Introduction

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impaired social interactions, difficulty with communication, and stereotypical behavior patterns often involving repetitive activities [1]. The pathophysiology of ASD involves dysregulation of neurotransmitter expression, aberrant neuronal migration, impaired neuronal intracellular calcium signaling, and disorganization of neuronal connectivity [2]. MIA inflammatory mouse models have been developed, which demonstrate autism-like behavior and were found to have elevation of the pro-inflammatory signal interleukin-6 (IL-6) with resultant fetal neuronal death, inhibition of neurogenesis, and impaired neuronal migration [4]. Genetic studies of ASD have identified mutations in scaffold proteins affecting synaptogenesis as well as mutations in neuronal intracellular calcium receptors resulting in abnormal axonal path-finding during brain development [5]

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Results

Conclusion