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.