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.
Highlights
Autism spectrum disorders (ASD) are a complex set of heterogeneous neurodevelopmental disorders characterized by core deficits in social behavior and communication, accompanied by restricted interests and repetitive behaviors, affecting up to 1 in 68 children[1,2]
We found hyperactive Akt-mTOR signaling in the hippocampus of Cntnap2−/− mice with RNA sequencing followed with biochemical analysis
Data were expressed as the mean ± sem. (j) The preference index of WT and Cntnap2−/− mice treated with saline, LY294002 or rapamycin
Summary
Autism spectrum disorders (ASD) are a complex set of heterogeneous neurodevelopmental disorders characterized by core deficits in social behavior and communication, accompanied by restricted interests and repetitive behaviors, affecting up to 1 in 68 children[1,2]. Abnormal mTOR signaling has been observed in several transgenic ASD animal models, such as Tsc1+/−, Tsc2+/−, Pten−/− and Fmr1−/− mice[4,5]. The inhibitor of mTOR signaling, rapamycin, has been demonstrated to be an effective therapeutics for impaired social interaction in Tsc1+/−, Tsc2+/−, Pten−/− mice and valproic acid-induced ASD animal model[4,8,9]. ASD are highly heritable, and genetic studies have revealed extraordinary heterogeneity with hundreds of rare risk genes, none accounting for more than 1% of ASD instances[10,11,12] It is still unknown if dysregulation of mTOR signaling is responsible for the ASD-related deficit caused by other gene mutations. Pharmacological inhibition of Akt-mTOR signaling reversibly rescued social deficit, but had no effect on hyperactivity and repetitive behaviors in Cntnap2−/− mice
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