Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
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DOI：
10.1523/jneurosci.5685-08.2009
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发表时间：
2009-02-11
期刊：
影响因子：
--
通讯作者：
Parada LF
中科院分区：
文献类型：
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作者：
Zhou J;Blundell J;Ogawa S;Kwon CH;Zhang W;Sinton C;Powell CM;Parada LF
PTEN（phosphatase and tensin homolog deleted on chromosome ten）是一种抑制磷脂酰肌醇-3激酶（phosphatidylinositol-3 kinase，PI 3 K）功能的脂质磷酸酶。PTEN功能的丧失导致AKT和下游效应物的组成性激活，并与许多人类癌症以及各种脑疾病（包括大头畸形、癫痫发作、Lhermitte-Duclos病和自闭症）相关。我们先前产生了一个条件性Pten基因敲除小鼠品系，在皮质和海马中有限的有丝分裂后神经元中存在Pten损失。Pten-null神经元发生神经元肥大和神经元极性丧失。突变小鼠表现出大头畸形和行为异常，让人联想到人类自闭症的某些特征。在这里，我们报告说，雷帕霉素，雷帕霉素复合物1（mTORC 1）的哺乳动物靶点的特异性抑制剂，可以防止和逆转神经元肥大，从而改善一个子集的PTEN相关的异常行为，提供证据表明，mTORC 1通路下游的PTEN是这种复杂的表型的关键。
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.