mTOR

The ability of cells to integrate signals from growth factors, nutrients, intermediate metabolism, and markers of cellular stress is key to cell development, function, and survival. In the nervous system, these signals are also critical for neuronal differentiation and synaptic plasticity. Among the multiple signal transduction pathways involved in these processes, increasing evidence points to a central role of those involving the mechanistic (previously known as mammalian) target of rapamycin (mTOR). mTOR is a ubiquitously expressed multieffector serine threonine protein kinase that forms 2 functionally distinct multiprotein signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTORC1 pathway controls cell growth and survival by regulating RNA translation, ribosomal biogenesis, nutrient transport, and autophagy. The tuberous sclerosis complex 1 (TSC) proteins, including TSC (hamartin) and TSC2 (tuberin), form a heterodimer that inhibits mTORC1 kinase activity. mTORC2 promotes cell cycle entry, controls cell morphology via its effects on the of the actin cytoskeleton, and inhibits apoptosis. In the nervous system, mTOR signals regulate neuronal survival and differentiation, dendritic arborization, axonal growth, synaptogenesis, and synaptic plasticity. Mutations in key regulatory genes affecting the mTORC1 pathway result in structural brain abnormalities and familial neoplasia syndromes associated with seizures, autism spectrum disorders, and cognitive dysfunction. One important example is tuberous sclerosis, due to TSC1 or TSC2 mutations. Excessive mTORC1 signaling may also be involved in aberrant plasticity underlying acquired conditions, including temporal lobe epilepsy and neurodegenerative disorders. Therefore, mTORC1 provides an important therapeutic target. There are several excellent reviews on the molecular mechanisms of mTOR signaling1–5 and its involvement in epilepsy and other neurologic disorders.6–14