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Downregulating the Canonical Wnt/β-catenin Signaling Pathway Attenuates the Susceptibility to Autism-like Phenotypes by Decreasing Oxidative Stress

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Abstract

Although a growing body of evidence supports the importance of the Wnt/β-catenin signaling pathway and oxidative stress in the pathogenesis of autism, it is unclear whether a relationship exists between the Wnt/β-catenin pathway and oxidative homeostasis. The present study examines the effects of sulindac, a small molecule inhibitor of the Wnt/β-catenin signaling pathway, on the oxidative status of rats that are prenatally exposed to valproic acid (VPA), which is used in an animal model of autism. Our data show that sulindac treatment downregulated the canonical Wnt/β-catenin signaling pathway by enhancing the expression of Glycogen Synthase Kinase 3β and attenuating the expression of β-catenin in comparison to levels in VPA-treated rats. Concomitantly, a marker of lipid peroxidation, 4-hydroxynonenal, was reduced as well. Sulindac treatment ameliorated the pain threshold, repetitive/stereotypic activity, learning and memory abilities and behavioral abnormalities of rats in our autism model. Our working model suggests that the upregulation of the Wnt/β-catenin signaling pathway induced by VPA administration during early pregnancy produces an imbalance of oxidative homeostasis that facilitates susceptibility to autism. This information may be instrumental in designing appropriate therapeutic regimens with small molecule inhibitors of the Wnt/β-catenin pathway for the treatment of autism-like behavioral phenotypes.

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Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 81171299). We thank Dr. Linyun Liu and Dr. Qian Huang for their excellent technical assistance in the behavioral tests of our rat model of autism. We also acknowledge Dr. Weigang Cui for assistance in image processing during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Yixueyuan Road 138, Shanghai, 200032, China

    Yinghua Zhang, Yan Sun, Fei Wang, Zhongping Wang, Yuwen Peng & Ruixi Li

  2. Department of Microbiology and Immunology, School of Basic Medical Sciences, Jiujiang University, Jiujiang, 332000, China

    Zhongping Wang

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  1. Yinghua Zhang
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  2. Yan Sun
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  3. Fei Wang
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Correspondence to Yuwen Peng or Ruixi Li.

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Zhang, Y., Sun, Y., Wang, F. et al. Downregulating the Canonical Wnt/β-catenin Signaling Pathway Attenuates the Susceptibility to Autism-like Phenotypes by Decreasing Oxidative Stress. Neurochem Res 37, 1409–1419 (2012). https://doi.org/10.1007/s11064-012-0724-2

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  • DOI: https://doi.org/10.1007/s11064-012-0724-2

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