Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

T.S. Zimmer, D.W.M. Broekaart, V.-E. Gruber, E.A. van Vliet, A. Mühlebner, E. Aronica

Research output: Contribution to JournalReview articleAcademicpeer-review

Abstract

Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

Original languageEnglish
Article number1028
Number of pages18
JournalFrontiers in Neurology
Volume11
DOIs
Publication statusPublished - 17 Sep 2020

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