Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent deficits in social communication and stereotyped behaviors. Although major advances in basic research on autism have been achieved in the past decade, and behavioral interventions can mitigate the difficulties that individuals with autism experience, little is known about the many fundamental issues of the interventions, and no specific medication has demonstrated efficiency for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH) is characterized by repeated exposure to lowered atmospheric pressure and oxygen levels, which triggers multiple physiological adaptations in the body. Here, using two mouse models of ASD, male Shank3B –/– and Fmr1 –/y mice, we found that IHH training at an altitude of 5000 m for 4 h per day, for 14 consecutive days, ameliorated autistic-like behaviors. Moreover, IHH training enhanced hypoxia inducible factor (HIF) 1α signaling in the dorsal raphe nucleus (DRN) and activated the DRN serotonergic neurons. Infusion of cobalt chloride into the DRN, to mimic IHH in increasing HIF1α expression or genetically knockdown PHD2 to upregulate HIF1α expression in the DRN serotonergic neurons, alleviated autistic-like behaviors in Shank3B –/– mice. In contrast, downregulation of HIF1α in DRN serotonergic neurons induced compulsive behaviors. Furthermore, upregulating HIF1α in DRN serotonergic neurons increased the firing rates of these neurons, whereas downregulation of HIF1α in DRN serotonergic neurons decreased their firing rates. These findings suggest that IHH activated DRN serotonergic neurons via upregulation of HIF1α signaling, and thus ameliorated autistic-like phenotypes, providing a novel therapeutic option for ASD. Significance Statement Autism spectrum disorder (ASD) affects more than 78 million individuals worldwide resulting in heavy social and economic burdens. However, no specific medication is effective for the core symptoms of ASD. Intermittent hypobaric hypoxia (IHH), a form of “living high–training low,” has been used to train pilots and mountaineers. Here, we found that IHH at an altitude of 5000 m for 4 h per day, for 14 consecutive days ameliorated autistic-like behavior in male Shank3B –/– and Fmr1 –/y mice. Moreover, IHH training increased the activation of serotonergic neurons in the dorsal raphe nucleus via upregulating HIF1α signaling, which contributes to the anti-autistic-like effect of IHH. These findings highlight the therapeutic potential of IHH in the treatment of ASD.