mTOR signaling in epilepsy: insights from malformations of cortical development.

Abstract

Over the past decade enhanced activation of the mammalian target of rapamycin (mTOR)-signaling cascade has been identified in focal malformations of cortical development (MCD) subtypes, which have been collectively referred to as "mTORopathies." Mutations in mTOR regulatory genes (e.g., TSC1, TSC2, AKT3, DEPDC5) have been associated with several focal MCD highly associated with epilepsy such as tuberous sclerosis complex (TSC), hemimegalencephaly (HME; brain malformation associated with dramatic enlargement of one brain hemisphere), and cortical dysplasia. mTOR plays important roles in the regulation of cell division, growth, and survival, and, thus, aberrant activation of the cascade during cortical development can cause dramatic alterations in cell size, cortical lamination, and axon and dendrite outgrowth often observed in focal MCD. Although it is widely believed that structural alterations induced by hyperactivated mTOR signaling are critical for epileptogenesis, newer evidence suggests that mTOR activation on its own may enhance neuronal excitability. Clinical trials with mTOR inhibitors have shown efficacy in the treatment of seizures associated with focal MCD.

• Authors: Peter B Crino
• Journal: Cold Spring Harbor perspectives in medicine (Cold Spring Harb Perspect Med) Vol. 5 Issue 4 (Apr 01 2015) ISSN: 2157-1422 [Electronic] United States
• PMID: 25833943 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Chemical References

• MTOR protein, human
• TOR Serine-Threonine Kinases

Topics

• Animals
• Disease Models, Animal
• Epilepsy (genetics)
• Humans
• Malformations of Cortical Development (classification, genetics, pathology)
• Mice
• Mutation
• Signal Transduction
• TOR Serine-Threonine Kinases (genetics)
• Tuberous Sclerosis (genetics)