Glutaminase 1 deficiency confined in forebrain neurons causes autism spectrum disorder-like behaviors

• Published in: Cell reports (Cambridge) Vol. 42; no. 7; p. 112712
• Main Authors: Ji, Chenhui, Tang, Yalin, Zhang, Yanyan, Huang, Xiaoyan, Li, Congcong, Yang, Yuhong, Wu, Qihui, Xia, Xiaohuan, Cai, Qingyuan, Qi, Xin-Rui, Zheng, Jialin C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2023; Elsevier
• Subjects: autism spectrum disorder; CP: Neuroscience; glutaminase 1; microglia; prefrontal cortex; synaptic neurotransmission; synaptic pruning; CP: Neuroscience; prefrontal cortex; synaptic pruning; glutaminase 1; autism spectrum disorder; microglia; synaptic neurotransmission
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112712

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD. [Display omitted] •Gls1CamKIIα-Cre mice manifest ASD-like behavioral phenotypes•Synaptic function, structure, and gene expression profile are altered in Gls1CamKIIα-Cre mice•Microglial synapse pruning is insufficient in Gls1CamKIIα-Cre mice•A low dose of LPS treatment rescues the molecular, physiological, and behavioral deficits Ji et al. find that loss of glutaminase 1 in forebrain neurons leads to autism spectrum disorder-like behaviors, accompanied by higher synaptic excitatory/inhibitory balance, spine density, and glutamate receptor gene expression, and lower synaptic pruning of microglia in the prefrontal cortex, which are significantly recovered by a low dose of LPS treatment.