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Pharmacological Inhibition of mTORC1 Suppresses Anatomical, Cellular, and Behavioral Abnormalities in Neural-Specific Pten Knock-Out Mice
Open accessAbstract
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.
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“Additionally in animal models of autism spectrum disorder (ASD), altered mTORC1 signaling contributes to the observed synaptic dysfunction and aberrant network connectivity (13,15,(21)(22)(23)(24)(25)(26)(27).”
From Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC) (2016) · cites this paper as [21]
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“Notably, pharmacological and genetic manipulations have successfully rescued both structural and behavioral phenotypes in PTEN86, FMR1 (ref. 87) and MECP2 (ref. 88) knockout mice.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [86]
In the citing paper
“That behavioral recovery in each of these rescue strategies was paralleled by reversal of spine pathologies underscores the importance of these structural perturbations in the pathogenesis of ASDs and comorbid disorders and the potential for the use of animal models in the development of therapeutics.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [86]
In the citing paper
“Rapamycin successfully reduced cognitive impairment and social behavior deficit in mouse models of tuberous sclerosis 61-63 and improved behavior in adult mice with a deletion of PTEN 64 .”
From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [64]
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“Experimental interventions, working through diverse genetic and pharmacological mechanisms, rescue subsets of behavioral abnormalities in these mouse models (31, 43, 48–52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [52]
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“Target strategies draw from therapeutics under investigation for other neurodevelopmental disorders and hypotheses emerging from mutations in synaptic genes identified in small numbers of individuals with autism spectrum disorders (43, 49, 52).”
From Negative allosteric modulation of the mGluR5 receptor reduces repetitive behaviors and rescues social deficits in mouse models of autism (2012) · cites this paper as [52]
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Metadata
- Authors
- Zhou, J., Blundell, J., Ogawa, S., Kwon, C.-H., Zhang, W., Sinton, C., Powell, C. M., & Parada, L. F.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- The University of Texas at Dallas (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-02-11
- Volume
- 29
- Issue
- 6
- Pages
- 1773-1783
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3904448
- OpenAlex
- W2017097994
- Cited by
- 441
- References
- 52
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 17 · 2023: 17 · 2022: 19 · 2021: 22 · 2020: 49 · 2019: 16 · 2018: 24 · 2017: 28 · 2016: 22 · 2015: 37 · 2014: 31 · 2013: 32 · 2012: 39
- FWCI
- 12.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Funders
- Autism Speaks (AS1270, AS2126)
- Simons Foundation
- National Institute of Mental Health (K08MH065975, R01MH081164)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD065290)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Keywords
- PTEN, mTORC1, rapamycin, neuronal hypertrophy, neuronal polarity, macrocephaly, autism-like behavior, postmitotic neurons, PI3K/Akt signaling, Lhermitte-Duclos disease, seizures, hippocampus, cortex
- MeSH terms
- Animals, Autistic Disorder, Female, Male, Mice, Inbred C57BL, Neurons, Transcription Factors, Mice, Knockout, Sirolimus, PTEN Phosphohydrolase, Mice
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