Poly(I:C)-exposed zebrafish shows autism-like behaviors which are ameliorated by fabp2 gene knockout

Jing Wu; Xueting Lin; Dian Wu; Binhong Yan; Mengyi Bao; Peilei Zheng; Jiangping Wang; Cuiwei Yang; Zhongxia Li; Xiaoming Jin; Kewen Jiang

doi:10.3389/fnmol.2022.1068019

Poly(I:C)-exposed zebrafish shows autism-like behaviors which are ameliorated by fabp2 gene knockout

Front Mol Neurosci. 2023 Jan 5:15:1068019. doi: 10.3389/fnmol.2022.1068019. eCollection 2022.

Authors

Jing Wu¹, Xueting Lin¹, Dian Wu¹, Binhong Yan², Mengyi Bao¹, Peilei Zheng², Jiangping Wang¹, Cuiwei Yang³, Zhongxia Li⁴, Xiaoming Jin^{5

6}, Kewen Jiang^{1

2}

Affiliations

¹ Department of Child Psychology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China.
² Department of Biobank Center, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China.
³ Department of Neurology, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center For Child Health, Hangzhou, China.
⁴ Department of Pediatrics, The Seventh Affiliated Hospital of Guangxi Medical University (Wuzhou GongRen Hospital), Wuzhou, Guangxi, China.
⁵ Indiana Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States.
⁶ Stark Neuroscience Research Institute, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States.

Abstract

Introduction: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders mainly representing impaired social communication. The etiology of ASD includes genetic and environmental risk factors. Rodent models containing ASD risk gene mutations or environmental risk factors, such as exposure to maternal inflammation, show abnormal behavior. Although zebrafish conserves many important brain structures of humans and has sophisticated and fine behaviors in social interaction, it is unknown whether the social behaviors of their offspring would be impaired due to exposure to maternal inflammation.

Methods: We exposed zebrafish to maternal immune activation (MIA) by injection with polyinosinic:polycytidylic acid [poly(I:C)], and screened their behaviors through social behavioral tests such as social preference and shoaling behavior tests. We compared phenotypes resulted from different ways of poly(I:C) exposure. RNA sequencing was performed to explore the differential expression genes (DEGs). Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis was performed with the detected DEGs to find the concentrated pathways. Finally, we knocked out the fatty acid-binding protein 2 (fabp2), a key node of the concentrated PPI network, to find its rescues on the altered social behavior.

Results: We reported here that MIA offspring born to mothers injected with poly(I:C) exhibited impaired social approach and social cohesion that mimicked human ASD phenotypes. Both maternal exposure and direct embryo exposure to poly(I:C) resulted in activations of the innate immune system through toll-like receptors 3 and 4. RNA-sequencing results from MIA brain tissues illustrated that the numbers of overexpressed genes were significantly more than that of underexpressed genes. GO and KEGG analyses found that MIA-induced DEGs were mainly concentrated in complement and coagulation cascade pathways. PPI network analyses suggested that villin-1 (vil1) pathway might play a key role in MIA-induced ASD. Knockout of fabp2 in F0 zebrafish rescued the social behavior deficits in MIA offspring.

Conclusions: Overall, our work established an ASD model with assessable behavior phenotype in zebrafish and provided key insights into environmental risk factor in ASD etiology and the influence of fabp2 gene on ASD-like behavior.

Keywords: F0 knockout; autism; fabp2; shoaling; social interaction; zebrafish.