Pharmacological inhibition of mTORCl suppresses anatomical, cellular, and behavioral abnormalities in neural-specific PTEN knock-out mice

Jing Zhou, Jacqueline Blundell, Shiori Ogawa, Chang Hyuk Kwon, Wei Zhang, Christopher Sinton, Craig M. Powell, Luis F. Parada

Research output: Contribution to journalArticle

256 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1773-1783
Number of pages11
JournalJournal of Neuroscience
Volume29
Issue number6
DOIs
StatePublished - Feb 11 2009

Fingerprint

Megalencephaly
Autistic Disorder
Knockout Mice
Hypertrophy
Multiple Hamartoma Syndrome
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinase
Pharmacology
Neurons
Brain Diseases
Sirolimus
Phosphoric Monoester Hydrolases
Hippocampus
Seizures
Chromosomes
Phenotype
Lipids
Neoplasms
mechanistic target of rapamycin complex 1
Inhibition (Psychology)

Keywords

  • Autism
  • Macrocephaly
  • Neuronal hypertrophy
  • Neuronal polarity
  • PTEN
  • Tuberous sclerosis complex

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Pharmacological inhibition of mTORCl suppresses anatomical, cellular, and behavioral abnormalities in neural-specific PTEN knock-out mice. / Zhou, Jing; Blundell, Jacqueline; Ogawa, Shiori; Kwon, Chang Hyuk; Zhang, Wei; Sinton, Christopher; Powell, Craig M.; Parada, Luis F.

In: Journal of Neuroscience, Vol. 29, No. 6, 11.02.2009, p. 1773-1783.

Research output: Contribution to journalArticle

Zhou, Jing ; Blundell, Jacqueline ; Ogawa, Shiori ; Kwon, Chang Hyuk ; Zhang, Wei ; Sinton, Christopher ; Powell, Craig M. ; Parada, Luis F. / Pharmacological inhibition of mTORCl suppresses anatomical, cellular, and behavioral abnormalities in neural-specific PTEN knock-out mice. In: Journal of Neuroscience. 2009 ; Vol. 29, No. 6. pp. 1773-1783.
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