mTOR Strikes Again: mTORC1 Activation Causes Epilepsy Independent of Overt Pathological Changes.

Commentary The mammalian target of rapamycin (mTOR) is a ubiquitous protein kinase that has received extensive attention in recent years as a potential mediator of epilepsy. mTOR, particularly a specific complex of proteins called mTORC1, regulates numerous cellular and physiologic functions, including protein synthesis , cell growth, proliferation, autophagy, and metabolism. Abnormal regulation of mTORC1 is most strongly implicated in promoting epilepsy in the genetic disease, tuberous sclerosis complex (TSC). However, there is now abundant evidence that mTORC1 may be involved in epileptogenesis in a variety of other types of epilepsies, including infantile spasms, neonatal hypoxic seizures, absence epilepsy, posttraumatic epilepsy, and acquired temporal lobe epilepsy (1). In TSC, the association between mTORC1 and epilepsy is strongly rooted in the primary genetic defect that causes this disease. Two genes, TSC1 and TSC2, have been linked to TSC. Since the protein products of TSC1 and TSC2, hamartin and tu-berin, normally function to inhibit mTORC1, mutations in TSC1 or TSC2 lead to disinhibited or abnormally elevated mTORC1 activity. Given the role of mTORC1 in stimulating cell growth and proliferation, hyperactivation of mTORC1 promotes excessive cell growth and tumor formation in various organs in TSC patients, including the skin, heart, kidneys, and brain. Identification of this pathophysiological mechanism has already led to the use of mTORC1 inhibitors for treating brain and kidney tumors in TSC patients. While the relationship of mTORC1 to tumors is relatively straightforward, the link to epilepsy in TSC is more complicated (1). Cortical tubers, the pathological hallmark of TSC, are most closely associated with epilepsy, as surgical removal of tubers can eliminate seizures in some TSC patients. Cortical tubers are considered malformations of cortical development, akin to focal cortical dysplasia. While tubers do not grow like true tumors, they do feature some tumor-like cellular features, such as glial proliferation and poorly differentiated cytomegal-ic cells, as well as biochemical evidence of increased mTORC1 activity. Although mTORC1 might also promote epileptogen-esis through tuber-independent mechanisms, the connection OBJECTIVE: Seizure development in Tuberous Sclerosis Complex (TSC) correlates with the presence of specific le-sions called cortical tubers. Moreover, heterozygous Tsc animal models do not show gross brain pathology and are seizure-free, suggesting that such pathology is a prerequisite for the development of epilepsy. However, cells within TSC lesions show increased activity of the target of rapamycin complex 1 (TORC1) pathway, and recent studies have implicated this pathway in non-TSC-related animal models of epilepsy and …