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The Journal of Neuroscience, May 21, 2008, 28(21):5422-5432; doi:10.1523/JNEUROSCI.0955-08.2008

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Neurobiology of Disease
Response of a Neuronal Model of Tuberous Sclerosis to Mammalian Target of Rapamycin (mTOR) Inhibitors: Effects on mTORC1 and Akt Signaling Lead to Improved Survival and Function

Lynsey Meikle,¹ Kristen Pollizzi,¹ Anna Egnor,¹ Ioannis Kramvis,² Heidi Lane,³ Mustafa Sahin,² and David J. Kwiatkowski¹

¹Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital and ²Department of Neurology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and ³Novartis Institutes for BioMedical Research, Oncology Basel, Novartis Pharma AG, CH-4002 Basel, Switzerland

Correspondence should be addressed to David J. Kwiatkowski, One Blackfan Circle, 6-216, Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. Email: dk{at}rics.bwh.harvard.edu

Tuberous sclerosis (TSC) is a hamartoma syndrome attributable to mutations in either TSC1 or TSC2 in which brain involvement causes epilepsy, mental retardation, and autism. We have reported recently (Meikle et al., 2007) a mouse neuronal model of TSC in which Tsc1 is ablated in most neurons during cortical development. We have tested rapamycin and RAD001 [40-O-(2-hydroxyethyl)-rapamycin], both mammalian target of rapamycin mTORC1 inhibitors, as potential therapeutic agents in this model. Median survival is improved from 33 d to more than 100 d; behavior, phenotype, and weight gain are all also markedly improved. There is brain penetration of both drugs, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream target of mTORC1. In addition, there is restoration of phospho-Akt and phospho-glycogen synthase kinase 3 levels in the treated mice, consistent with restoration of Akt function. Neurofilament abnormalities, myelination, and cell enlargement are all improved by the treatment. However, dysplastic neuronal features persist, and there are only modest changes in dendritic spine density and length. Strikingly, mice treated with rapamycin or RAD001 for 23 d only (postnatal days 7–30) displayed a persistent improvement in phenotype, with median survival of 78 d. In summary, rapamycin/RAD001 are highly effective therapies for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signaling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that rapamycin/RAD001 may have benefit in the treatment of TSC brain disease, including infantile spasms.

Key words: tuberous sclerosis; TSC; TSC1; TSC2; rapamycin; RAD001

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Received Jan. 14, 2008; revised April 6, 2008; accepted April 7, 2008.

Correspondence should be addressed to David J. Kwiatkowski, One Blackfan Circle, 6-216, Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115. Email: dk{at}rics.bwh.harvard.edu

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