期刊
DEVELOPMENTAL NEUROSCIENCE
卷 34, 期 2-3, 页码 198-209出版社
KARGER
DOI: 10.1159/000337229
关键词
Pten; Mammalian target of rapamycin; Glutamate; Autism; Seizure; NMDA receptor; Epilepsy
资金
- New Jersey Governor's Council for Medical Research and Treatment of Autism
- Citizens United for Research in Epilepsy
- Epilepsy Foundation
- NIH/NINDS [RO1 NS039943, NS049427]
- Foundation of UMDNJ Society of Research Scholars
- Leathem Steinetz Stauber McCallum 2011 Summer Research Award
The phosphatase and tensin homolog located on chromosome 10 (PTEN) suppresses the activity of the phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway, a signaling cascade critically involved in the regulation of cell proliferation and growth. Human patients carrying germ line PTEN mutations have an increased predisposition to tumors, and also display a variety of neurological symptoms and increased risk of epilepsy and autism, implicating PTEN in neuronal development and function. Consistently, loss of Pten in mouse neural cells results in ataxia, seizures, cognitive abnormalities, increased soma size and synaptic abnormalities. To better understand how Pten regulates the excitability of principal forebrain neurons, a factor that is likely to be altered in cognitive disorders, epilepsy and autism, we generated a novel conditional knockout mouse line (NEX-Pten) in which Cre, under the control of the NEX promoter, drives the deletion of Pten specifically in early post-mitotic, excitatory neurons of the developing forebrain. Homozygous mutant mice exhibited a massive enlargement of the forebrain, and died shortly after birth due to excessive mTOR activation. Analysis of the neonatal cerebral cortex further identified molecular defects resulting from Pten deletion that likely affect several aspects of neuronal development and excitability. Copyright (C) 2012 S. Karger AG, Basel
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