The role of glia in epilepsy, intellectual disability, and other neurodevelopmental disorders in tuberous sclerosis complex

Background: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by severe neurological manifestations, including epilepsy, intellectual disability, autism, and a range of other behavioral and psychiatric symptoms, collectively referred to as TSC-Associated neuropsychiatric disorders (TAND). Various tumors and hamartomas affecting different organs are the pathological hallmarks of the disease, especially cortical tubers of the brain, but specific cellular and molecular abnormalities, such as involving the mechanistic target of rapamycin (mTOR) pathway, have been identified that also cause or contribute to neurological manifestations of TSC independent of gross structural lesions. In particular, while neurons are immediate mediators of neurological symptoms, different types of glial cells have been increasingly recognized to play important roles in the phenotypes of TSC. Main body: This review summarizes the literature supporting glial dysfunction from both mouse models and clinical studies of TSC. In particular, evidence for the role of astrocytes, microglia, and oligodendrocytes in the pathophysiology of epilepsy and TAND in TSC is analyzed. Therapeutic implications of targeting glia cells in developing novel treatments for the neurological manifestations of TSC are also considered. Conclusions: Different types of glial cells have both cell autonomous effects and interactions with neurons and other cells that are involved in the pathophysiology of the neurological phenotype of TSC. Targeting glial-mediated mechanisms may represent a novel therapeutic approach for epilepsy and TAND in TSC patients.