Intermittent Hypobaric Hypoxia Ameliorates Autistic-Like Phenotypes in Mice

Area of Science:

• Neuroscience
• Genetics
• Physiology

Background:

• Autism spectrum disorder (ASD) presents challenges in social communication and behavior.
• Current interventions for ASD have limitations, with no specific medication targeting core symptoms.
• Intermittent hypobaric hypoxia (IHH) involves exposure to reduced atmospheric pressure and oxygen, inducing physiological adaptations.

Purpose of the Study:

• To investigate the therapeutic potential of IHH for ASD.
• To explore the underlying mechanisms of IHH's effects on ASD-like behaviors in mouse models.

Main Methods:

• Two mouse models of ASD (Shank3B-/- and Fmr1-/y) were subjected to IHH training (5,000m, 4h/day for 14 days).
• Hypoxia-inducible factor 1α (HIF1α) expression and serotonergic neuron activity in the dorsal raphe nucleus (DRN) were analyzed.
• Pharmacological and genetic manipulations were used to modulate HIF1α levels in DRN serotonergic neurons.

Main Results:

• IHH training significantly ameliorated autistic-like behaviors in both mouse models.
• IHH enhanced HIF1α expression and activated DRN serotonergic neurons.
• Modulating HIF1α in DRN serotonergic neurons directly affected ASD-like and compulsive behaviors, correlating with neuronal firing rates.

Conclusions:

• IHH activates DRN serotonergic neurons through HIF1α upregulation, alleviating autistic-like phenotypes.
• This study identifies a novel therapeutic strategy for ASD, highlighting the role of the HIF1α-serotonin pathway.