Elevation of H2S Underlies Social Deficits in Environmental Factor Double-Hit Autism Model
Hongyu Ma1,2,3,4 · Qing Xu3,4 · Songqi Dong3,4 · Mengxin Guo3,4 · Hanze Liu3,4,5 · Taozhi Wang6 · Mengmeng Wang3,4 · Yazhou Wang3,4 · Shengxi Wu1,2,3,4
1 Department of Neurobiology, Hebei Medical University, Shijiazhuang 050017, China
2 The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang 050017, China
3 Department of Neurobiology, School of Basic Medicine, Fourth Military Medical University, Xi’an 710032, China
4 The Shaanxi Province Key Laboratory of Brain Function Analysis and Modulation, Xi’an 710032, China
5 Department of Neurobiology, Medical College of Yan’an University, Yan’an 716000, China
6 Department of Anesthesiology and Perioperative Medicine, Key Laboratory of Anesthesiology, Ministry of Education, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
Abstract
The underlying mechanism for the environmental factor-induced autism spectrum disorder (ASD) remains largely unclear. Considering the recent reports that mitochondria-associated amino acid metabolism contributes to ASD development, we explored the roles of hydrogen sulfide (H2S), a gaseous product of sulfur-containing amino acid metabolism, in the social deficits of ASD mice induced by the environmental factor double-hit (DH). We detected synaptic and mitochondrial dysfunction, elevation of H2S, dysregulation of sulfur-containing metabolites, and upregulation of cystathionine-β-synthase (CBS) in the anterior cingulate cortex of DH mice. Inhibiting mitochondrial function induced H2S accumulation in wild-type neurons, whereas introducing healthy mitochondria suppressed H2S levels in DH neurons. Knocking down CBS or restricting sulfur intake significantly ameliorated synaptic dysfunction, social impairments, and anxiety-like behaviors in DH mice. Similar H2S accumulation was detected in human DH neurons and ASD patients. Our data demonstrated a role of H2S overload in the social dysfunction of environmental factor-induced ASD.
Keywords
Autism spectrum disorder; H2S; Social behavior; Synaptic dysfunction; Sulfur amino acid restriction
