title: Mechanisms regulating neuronal excitability and seizure development following mTOR pathway hyperactivation.
abstract: The phosphatidylinositol-3-kinase/phosphatase and tensin homolog (PTEN)-mammalian target of rapamycin (mTOR) pathway regulates a variety of neuronal functions, including cell proliferation, survival, growth, and plasticity. Dysregulation of the pathway is implicated in the development of both genetic and acquired epilepsies. Indeed, several causal mutations have been identified in patients with epilepsy, the most prominent of these being mutations in PTEN and tuberous sclerosis complexes 1 and 2 (TSC1, TSC2). These genes act as negative regulators of mTOR signaling, and mutations lead to hyperactivation of the pathway. Animal models deleting PTEN, TSC1, and TSC2 consistently produce epilepsy phenotypes, demonstrating that increased mTOR signaling can provoke neuronal hyperexcitability. Given the broad range of changes induced by altered mTOR signaling, however, the mechanisms underlying seizure development in these animals remain uncertain. In transgenic mice, cell populations with hyperactive mTOR have many structural abnormalities that support recurrent circuit formation, including somatic and dendritic hypertrophy, aberrant basal dendrites, and enlargement of axon tracts. At the functional level, mTOR hyperactivation is commonly, but not always, associated with enhanced synaptic transmission and plasticity. Moreover, these populations of abnormal neurons can affect the larger network, inducing secondary changes that may explain paradoxical findings reported between cell and network functioning in different models or at different developmental time points. Here, we review the animal literature examining the link between mTOR hyperactivation and epileptogenesis, emphasizing the impact of enhanced mTOR signaling on neuronal form and function.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA.
authors.forename: Candi L
authors.initials: CL
authors.lastname: Lasarge
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center Cincinnati, OH, USA ; Department of Anesthesia, University of Cincinnati Cincinnati, OH, USA ; Department of Pediatrics, University of Cincinnati Cincinnati, OH, USA.
authors.forename: Steve C
authors.initials: SC
authors.lastname: Danzer
keywords: PTEN; TSC; autism; epilepsy; granule cells; hippocampus; mTOR; neurogenesis