Rapamycin improves social and stereotypic behavior abnormalities induced by pre‐mitotic neuronal subset specific Pten deletion

The mechanistic target of rapamycin (mTOR) pathway is a signaling system integral to neural growth and migration. In both patients and rodent models, mutations to the phosphatase and tensin homolog gene (PTEN) on chromosome 10 results in hyperactivation of the mTOR pathway, as well as seizures, intellectual disabilities and autistic behaviors. Rapamycin, an inhibitor of mTOR, can reverse the epileptic phenotype of neural subset specific Pten knockout (NS‐Pten KO) mice, but its impact on behavior is not known. To determine the behavioral effects of rapamycin, male and female NS‐Pten KO and wildtype (WT) mice were assigned as controls or administered 10 mg/kg of rapamycin for 2 weeks followed by behavioral testing. Rapamycin improved social behavior in both genotypes and stereotypic behaviors in NS‐Pten KO mice. Rapamycin treatment resulted in a reduction of several measures of activity in the open field test in both genotypes. Rapamycin did not reverse the reduced anxiety behavior in KO mice. These data show the potential clinical use of mTOR inhibitors by showing its administration can reduce the production of autistic‐like behaviors in NS‐Pten KO mice. Inhibition of the mechanistic target of rapamycin (mTOR) pathway through rapamycin during adolescent improved stereotypy and social behavior in neural subset specific Pten (NS‐Pten) knockout mice. Rapamycin reduced locomotor behavior but did not impact anxiety behavior in wildtype mice.