mTORC1 inhibition reverses neurological abnormalities in neural Pten-knockout mice.
| Evidence tier | C Animal in vivo |
| Study type | 4 - Animal Study |
| Model system | Mouse (Pten KO) |
| Journal | The Journal of neuroscience |
| Year | 2009 |
| Peer reviewed | Yes |
| Source | DOI 10.1523/JNEUROSCI.5685-08.2009 · PMID 19211884 · Free full text (PMC3904448) |
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.
| Intervention | mTORC1 inhibition (rapamycin) |
| Target | mTORC1 / PTEN-Akt |
| Model | Mouse (neural Pten KO) |
| Effect | mTORC1 inhibition suppresses anatomical, cellular and behavioral abnormalities in Pten-null brain (macrocephaly, seizures, autism-like) |