SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice

• Published in: Cell death & disease Vol. 13; no. 7; p. 638
• Main Authors: Xiang, Ludan, Wu, Qian, Sun, Huankun, Miao, Xuemeng, Lv, Zhaoting, Liu, Huitao, Chen, Lan, Gu, Yanrou, Chen, Jianjun, Zhou, Siyao, Jiang, Huixia, Du, Siyu, Zhou, Yixin, Dong, Hui, Fan, Yiren, Miao, Shuangda, Lu, Qi, Chang, Liyun, Wang, Hui, Lu, Yi, Xu, Xingxing, Wang, Wei, Huang, Zhihui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-07-2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 14/19; 14/34; 45/77; 45/91; 631/378/1689/1373; 631/378/1934; 64/60; 82/1; 82/51; 82/80; 96/2; Animals; Antibodies; Apoptosis; Armadillo Domain Proteins - genetics; Autism; Autism Spectrum Disorder - genetics; Autistic Disorder - genetics; Autistic Disorder - pathology; Biochemistry; Biomedical and Life Sciences; c-Fos protein; Caspase-3; Cell Biology; Cell Culture; Cytoskeletal Proteins - genetics; Disease Models, Animal; Immunology; Interneurons; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurodevelopmental disorders; Neurons - metabolism; Parvalbumin; Parvalbumins - metabolism; Pathogenesis; Postsynaptic density proteins; Rodents; Social behavior; γ-Aminobutyric acid
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05083-2

Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1
PV
-CKO) mice. SARM1
PV
-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1
PV
-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1
PV
-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1
PV
-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.