2. Academic Validation
  3. Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice

Suppression of Akt-mTOR pathway rescued the social behavior in Cntnap2-deficient mice

  • Sci Rep. 2019 Feb 28;9(1):3041. doi: 10.1038/s41598-019-39434-5.
Xiaoliang Xing 1 2 3 4,  Jing Zhang 1 3 4,  Kunyang Wu 1 3 4,  Beibei Cao 1 3 4,  Xianfeng Li 1 3 4,  Fang Jiang 1 3 4,  Zhengmao Hu 1 4 5,  Kun Xia 1 4 5,  Jia-Da Li 6 7 8 9
Affiliations

Affiliations

  • 1 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, P. R. China.
  • 2 Hunan University of Medicine, Huaihua, 418000, Hunan, P. R. China.
  • 3 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, 410078, Hunan, P. R. China.
  • 4 Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, P. R. China.
  • 5 Collaborative Innovation Center for Genetics and Development, Shanghai, 200000, China.
  • 6 Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, 410078, Hunan, P. R. China. lijiada@sklmg.edu.cn.
  • 7 Hunan Key Laboratory of Animal Models for Human Diseases, Changsha, 410078, Hunan, P. R. China. lijiada@sklmg.edu.cn.
  • 8 Hunan Key Laboratory of Medical Genetics, Changsha, 410078, Hunan, P. R. China. lijiada@sklmg.edu.cn.
  • 9 Collaborative Innovation Center for Genetics and Development, Shanghai, 200000, China. lijiada@sklmg.edu.cn.
PMID: 30816216 DOI: 10.1038/s41598-019-39434-5
Abstract

Autism spectrum disorders (ASD) form a heterogeneous, neurodevelopmental syndrome characterized by deficits in social interactions and repetitive behavior/restricted interests. Dysregulation of mTOR signaling has been implicated in the pathogenesis of certain types of ASD, and inhibition of mTOR by rapamycin has been demonstrated to be an effective therapeutics for impaired social interaction in Tsc1+/-, Tsc2+/-, Pten-/- mice and valproic acid-induced ASD animal models. However, it is still unknown if dysregulation of mTOR signaling is responsible for the ASD-related deficit caused by other genes mutations. Contactin associated protein-like 2 (CNTNAP2) is the first widely replicated autism-predisposition gene. Mice deficient in Cntnap2 (Cntnap2-/- mice) show core ASD-like phenotypes, and have been demonstrated as a validated model for ASD-relevant drug discovery. In this study, we found hyperactive Akt-mTOR signaling in the hippocampus of Cntnap2-/- mice with RNA Sequencing followed with biochemical analysis. Treatment with Akt Inhibitor LY294002 or mTOR Inhibitor rapamycin rescued the social deficit, but had no effect on hyperactivity and repetitive behavior/restricted behavior in Cntnap2-/- mice. We further showed that the effect of LY294002 and rapamycin on social behaviors is reversible. Our results thus identified hyperactive Akt-mTOR signaling pathway as a therapeutic target for abnormal social behavior in patients with dysfunction of CNTNAP2.

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