Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice. Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.
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Acknowledgements
We thank colleagues and students in Shi Group of JNU-HKUST Joint Lab for Neuroscience and Innovative Drug Research for constructive discussions on this study. This study was supported by the Key-Area Research and Development Program of Guangdong Province (2019B030335001), the National Natural Science Foundation of China (82071535, 81971079, 82101240), Guangdong Basic and Applied Basic Research Foundation (2020A1515110570), and China Postdoctoral Science Foundation (2021M691245).
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This work was supported by the Key-Area Research and Development Program of Guangdong Province Grant No 2019B030335001, the National Natural Science Foundation of China Grant Nos 82071535, 81971079, 82101240, Guangdong Basic and Applied Basic Research Foundation Grant No 2020A1515110570, and China Postdoctoral Science Foundation Grant No 2021M691245.
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Conceptualization: DG, KL, LS; Resources: KL, LS. Methodology: XY, MG; Validation: DG, XC; Formal analysis: DG, XY, MG, XC, YT; Investigation: DG, XY, MG, XC, YT, LLS; Writing—Original Draft: DG, XY, MG; Writing—Review & Editing: DG, KL, LS; Visualization: DG, XY, KL, LS; Supervision: DG, KL, LS; Funding acquisition: DG, KL, LS. Project administration: LS.
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Guo, D., Yang, X., Gao, M. et al. Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age. Cell Mol Neurobiol 43, 1129–1146 (2023). https://doi.org/10.1007/s10571-022-01233-4
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DOI: https://doi.org/10.1007/s10571-022-01233-4