title: Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
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 (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.
authors.affiliation: Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, and University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blundell
authors.forename: Shiori
authors.initials: S
authors.lastname: Ogawa
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Sinton
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism* / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: C519509:Crtc1 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D020123:Sirolimus