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The Journal of Neuroscience, February 11, 2009, 29(6):1773-1783; doi:10.1523/JNEUROSCI.5685-08.2009

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Cellular/Molecular
Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-Specific Pten Knock-Out Mice

Jing Zhou,¹ Jacqueline Blundell,² Shiori Ogawa,³ Chang-Hyuk Kwon,¹ Wei Zhang,¹ Christopher Sinton,³ Craig M. Powell,^2,4 and Luis F. Parada¹

¹Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, and Departments of ²Neurology, ³Internal Medicine, and ⁴Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Luis F. Parada, Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390. Email: luis.parada{at}utsouthwestern.edu

PTEN (phosphatase and tensin homolog deleted on chromosome ten) is a lipid phosphatase that counteracts the function of phosphatidylinositol-3 kinase (PI3K). Loss of function of PTEN results in constitutive activation of AKT and downstream effectors and correlates with many human cancers, as well as various brain disorders, including macrocephaly, seizures, Lhermitte–Duclos disease, and autism. We previously generated a conditional Pten knock-out mouse line with Pten loss in limited postmitotic neurons in the cortex and hippocampus. Pten-null neurons developed neuronal hypertrophy and loss of neuronal polarity. The mutant mice exhibited macrocephaly and behavioral abnormalities reminiscent of certain features of human autism. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin complex 1 (mTORC1), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORC1 pathway downstream of PTEN is critical for this complex phenotype.

Key words: PTEN; tuberous sclerosis complex; autism; macrocephaly; neuronal hypertrophy; neuronal polarity

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Received Nov. 28, 2008; accepted Dec. 23, 2008.

Correspondence should be addressed to Luis F. Parada, Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, TX 75390. Email: luis.parada{at}utsouthwestern.edu

This article has been cited by other articles:

				J. Zhou, J. Brugarolas, and L. F. Parada Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1 Hum. Mol. Genet., November 15, 2009; 18(22): 4428 - 4441. [Abstract] [Full Text] [PDF]

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