title: Prenatal rapamycin results in early and late behavioral abnormalities in wildtype C57BL/6 mice.
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.
authors.affiliation: Department of Neurology, The F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue CLS13074, Boston, MA 02115, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Tsai
authors.forename: Emily
authors.initials: E
authors.lastname: Greene-Colozzi
authors.forename: June
authors.initials: J
authors.lastname: Goto
authors.forename: Stefanie
authors.initials: S
authors.lastname: Anderl
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
authors.forename: Mustafa
authors.initials: M
authors.lastname: Sahin
mesh_terms: D000818:Animals; D001007:Anxiety / Q000209:etiology; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D018811:Maternal Exposure; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000209:etiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000523:psychology*; D012018:Reflex; D020123:Sirolimus / Q000009:adverse effects*; D013997:Time Factors; D014402:Tuberous Sclerosis / Q000188:drug therapy; D014828:Vocalization, Animal
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus