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The Journal of Neuroscience, May 23, 2007, 27(21):5546-5558; doi:10.1523/JNEUROSCI.5540-06.2007

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Neurobiology of Disease
A Mouse Model of Tuberous Sclerosis: Neuronal Loss of Tsc1 Causes Dysplastic and Ectopic Neurons, Reduced Myelination, Seizure Activity, and Limited Survival

Lynsey Meikle,^1 * Delia M. Talos,^2 * Hiroaki Onda,¹ Kristen Pollizzi,¹ Alexander Rotenberg,² Mustafa Sahin,² Frances E. Jensen,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

Correspondence should be addressed to either of the following: 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; or Frances E. Jensen, Enders 348, Neurology, Children's Hospital, Boston, 300 Longwood Avenue, Boston, MA 02115, E-mail: Email: frances.jensen{at}childrens.harvard.edu

Tuberous sclerosis (TSC) is a hamartoma syndrome caused by mutations in TSC1 or TSC2 in which cerebral cortical tubers and seizures are major clinical issues. We have engineered mice in which most cortical neurons lose Tsc1 expression during embryonic development. These Tsc1 mutant mice display several neurological abnormalities beginning at postnatal day 5 with subsequent failure to thrive and median survival of 35 d. The mice also display clinical and electrographic seizures both spontaneously and with physical stimulation, and some seizures end in a fatal tonic phase. Many cortical and hippocampal neurons are enlarged and/or dysplastic in the Tsc1 mutant mice, strongly express phospho-S6, and are ectopic in multiple sites in the cortex and hippocampus. There is a striking delay in myelination in the mutant mice, which appears to be caused by an inductive neuronal defect. This new TSC brain model replicates several features of human TSC brain lesions and implicates an important function of Tsc1/Tsc2 in neuronal development.

Key words: tuberous sclerosis; TSC1; mTOR; dysplastic neuron; ectopic neurons; seizures

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Received Dec. 21, 2006; revised April 13, 2007; accepted April 14, 2007.

Correspondence should be addressed to either of the following: 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; or Frances E. Jensen, Enders 348, Neurology, Children's Hospital, Boston, 300 Longwood Avenue, Boston, MA 02115, E-mail: Email: frances.jensen{at}childrens.harvard.edu

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