TY - JOUR
T1 - Pharmacological inhibition of mTORCl suppresses anatomical, cellular, and behavioral abnormalities in neural-specific PTEN knock-out mice
AU - Zhou, Jing
AU - Blundell, Jacqueline
AU - Ogawa, Shiori
AU - Kwon, Chang Hyuk
AU - Zhang, Wei
AU - Sinton, Christopher
AU - Powell, Craig M.
AU - Parada, Luis F.
PY - 2009/2/11
Y1 - 2009/2/11
N2 - 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 (mTORCl), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORCl pathway downstream of PTEN is critical for this complex phenotype.
AB - 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 (mTORCl), can prevent and reverse neuronal hypertrophy, resulting in the amelioration of a subset of PTEN-associated abnormal behaviors, providing evidence that the mTORCl pathway downstream of PTEN is critical for this complex phenotype.
KW - Autism
KW - Macrocephaly
KW - Neuronal hypertrophy
KW - Neuronal polarity
KW - PTEN
KW - Tuberous sclerosis complex
UR - http://www.scopus.com/inward/record.url?scp=60849109211&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=60849109211&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.5685-08.2009
DO - 10.1523/JNEUROSCI.5685-08.2009
M3 - Article
C2 - 19211884
AN - SCOPUS:60849109211
SN - 0270-6474
VL - 29
SP - 1773
EP - 1783
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 6
ER -