Tuberous sclerosis and epilepsy: Role of astrocytes

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is among the most common genetic causes of epilepsy. Focal brain lesions in TSC, known as cortical tubers, have been implicated in promoting epileptogenesis in TSC. Histological, cellular, and molecular abnormalities in astrocytes are characteristic features of tubers and perituberal cortex, suggesting that astrocyte dysfunction may contribute to the pathophysiology of epilepsy in TSC. Numerous astrocytes can be seen histologically in tubers expressing glial fibrillary acidic and S100 proteins. In some analyses, astrocytes exhibit enhanced activation of the mammalian target of rapamycin suggesting a link between TSC1 and TSC2 mutations and astrocytic proliferation. Astrocytic proliferation in subependymal giant cell astrocytoma is associated with progressive growth and compression of surrounding brain structures by these lesions. Increased numbers of enlarged astrocytes has been observed in several TSC mouse models and may be intimately linked to epileptogenesis. Impairment of astrocytic buffering mechanisms for glutamate and potassium has been identified in TSC animal models and human tuber tissue and likely promotes neuronal excitability and seizures in TSC. Targeting these defects in astrocytes may represent a novel therapeutic strategy for epilepsy in patients with TSC.

Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders

“…In addition, recordings in patients suggest tubers are electrically silent, focusing the search for epileptic foci on surrounding tissue (Schwartzkroin and Wenzel, 2012). Deletion of Tsc1 in glia and/or neural progenitors produces seizures (for review see Wong and Crino, 2012), as does deletion in forebrain excitatory neurons, suggesting multiple potential pathways for generating seizures from loss of function of the TS complex. One recent study performed detailed physiological analyses following sparse cre-mediated deletion of a conditional Tsc1 allele in hippocampal neurons.…”

Immunity and Inflammation in Epilepsy

“…1). Glia activation occurs also in genetic models of epilepsy, such as in rats with spike-and-wave discharges mimicking absence seizures (Akin et al 2011), models of tuberous sclerosis (Wong and Crino 2012), and progressive myoclonus epilepsy of Unverricht -Lundborg type 1 (Tegelberg et al 2012;Joensuu et al 2014). Notably, glia activation occurs during epileptogenesis (i.e., the phase that precedes the onset of the disease and accompanies its progression) (Pitkanen and Engel 2014) both in symptomatic and genetic epilepsy models, and is maintained in the chronic epilepsy phase (when the disease is established).…”

Animal models of tumour-associated epilepsy

“…Moreover, vigabatrin -one of the most effective anticonvulsant drugs in TSC -inhibited both seizures and mTOR activation in this model . The role of astrocytes in TSC-associated epilepsy has recently been reviewed (Wong and Crino, 2012).…”