Xenon improves autism-like behaviors in mice through potentiation of PVT-CeA glutamatergic neurotransmission

Autism spectrum disorder (ASD) is a common neurodevelopmental disease with no currently effective treatments. In this study, Xenon (Xe), a noble gas used clinically as an anesthetic and a neuroprotectant, has been investigated for its potential therapeutic effects in ASD. Two genetic ASD mouse models (Mef2c mutant and Shank3-/- mice) were exposed to a low concentration of xenon (25%) mixed with oxygen (30%) and balanced with nitrogen for a single exposure of 30 min or for 10 min per day for 10 days. These Xe exposure paradigms rescued ASD-like behaviors in both male and female mice. The behavioral improvements persisted for up to 10 days following termination of the 10-day exposure paradigm. Mechanistically, Xe reduced glutamic acid decarboxylase expression in the inhibitory neurons (verified with RNAseq) of the paraventricular thalamic nucleus (PVT) and decreased GABA release during social interaction. Targeted infusion of the GABAA receptor agonist muscimol into the PVT abolished the Xe-mediated behavioral improvements. Reduced GABAergic transmission following Xe exposure increased PVT glutamatergic neuronal activity. Chemogenetic inhibition of these neurons eliminated the therapeutic effects of Xe, whereas chemogenetic activation mimicked the Xe-induced behavioral improvements. Furthermore, opto-inhibition of PVT glutamatergic projections to the central amygdala (CeA) blocked Xe-mediated behavioral improvement. Opto-activation of the PVT-CeA glutamatergic circuit reversed ASD-like behaviors. These findings demonstrate that Xe ameliorates ASD-like phenotypes in mouse models by modulating the PVT Glu-CeA circuit, supporting Xe as a novel potential therapy for ASD.