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Prenatal Rapamycin Results in Early and Late Behavioral Abnormalities in Wildtype C57Bl/6 Mice

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Abstract

Mammalian target of rapamycin (mTOR) signaling has been shown to be deregulated in a number of genetic, neurodevelopmental disorders including Tuberous Sclerosis Complex, Neurofibromatosis, Fragile X, and Rett syndromes. As a result, mTOR inhibitors, such as rapamycin and its analogs, offer potential therapeutic avenues for these disorders. Some of these disorders—such as Tuberous Sclerosis Complex—can be diagnosed prenatally. Thus, prenatal administration of these inhibitors could potentially prevent the development of the devastating symptoms associated with these disorders. To assess the possible detrimental effects of prenatal rapamycin treatment, we evaluated both early and late behavioral effects of a single rapamycin treatment at embryonic day 16.5 in wildtype C57Bl/6 mice. This treatment adversely impacted early developmental milestones as well as motor function in adult animals. Rapamycin also resulted in anxiety-like behaviors during both early development and adulthood but did not affect adult social behaviors. Together, these results indicate that a single, prenatal rapamycin treatment not only adversely affects early postnatal development but also results in long lasting negative effects, persisting into adulthood. These findings are of importance in considering prenatal administration of rapamycin and related drugs in the treatment of patients with neurogenetic, neurodevelopmental disorders.

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Acknowledgments

We thank Michela Fagiolini, Paul Rosenberg, and Jacqueline Crawley for assistance with behavioral experiments. P. T. T. received support from the Developmental Neurology Training Grant (T32 NS007473), American Academy of Neurology, and the Nancy Lurie Marks Family Foundation. This work and M. S. are supported by the John Merck Scholars Fund, Boston Children’s Hospital Translational Research Program, and Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (P30 HD18655). DJK was supported by NIH NINDS 2R37NS031535-14.

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Authors and Affiliations

  1. Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children’s Hospital, 300 Longwood Avenue CLS13074, Boston, MA, 02115, USA

    Peter T. Tsai, Emily Greene-Colozzi & Mustafa Sahin

  2. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    June Goto, Stefanie Anderl & David J. Kwiatkowski

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  1. Peter T. Tsai
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  2. Emily Greene-Colozzi
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  3. June Goto
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  4. Stefanie Anderl
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  5. David J. Kwiatkowski
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  6. Mustafa Sahin
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Corresponding author

Correspondence to Mustafa Sahin.

Additional information

Edited by Pierre Roubertoux.

Peter T. Tsai and Emily Greene-Colozzi contributed equally to this study.

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Tsai, P.T., Greene-Colozzi, E., Goto, J. et al. Prenatal Rapamycin Results in Early and Late Behavioral Abnormalities in Wildtype C57Bl/6 Mice. Behav Genet 43, 51–59 (2013). https://doi.org/10.1007/s10519-012-9571-9

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  • DOI: https://doi.org/10.1007/s10519-012-9571-9

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