Tuberous sclerosis: A primary pathology of astrocytes?

Abstract

SUMMARYPurpose: Cortical tubers are epileptogenic lesions in patients with tuberous sclerosis complex (TSC). Giant cells and dysplastic neurons are pathological hallmarks of cortical tubers. Severe astrogliosis, which is invariably present in tubers, has attracted much less attention. We hypothesize that the development of astrogliosis in cortical tubers constitutes a primary pathology of astrocytes and is directly related to TSC 1/2 mutations. Methods: To begin to test this hypothesis, we performed immunohistochemical and electron microscopic analysis of brain tuber tissue resected from epileptic TSC patients. We compared alterations in tuber astrocytes to those found in other acute and chronic human epilepsy pathologies. Results: We found that astrogliosis in tubers is comprised of a mixture of "gliotic" and "reactive" astrocytes. The majority of tuber astrocytes are "gliotic" astrocytes that are morphologically and immunophenotypically similar to astrocytes in areas of gliosis in hippocampal sclerosis (HS). However, specific immunostaining features differentiate TSC gliosis from HS gliosis. "Reactive" tuber astrocytes are large-sized, vimentin positive cells in the vicinity of giant cells that show activation of the mammalian target of rapamycin (mTOR) pathway, consistent with mutated TSC gene function. These cells resemble acutely reactive human astrocytes seen in tissue resected from depth electrode implantation patients. Oligodendrocytes and NG2 expressing glial cells do not have any detectable alterations within tubers. Conclusion: We conclude that astrocytes are the type of glial cell selectively impacted in cortical tuber pathology. We propose that tubers may be dynamic lesions, with progression of astrocytes over time from "reactive" to "gliotic." Tuber astrogliosis in TSC may represent a genetic "model" of gliosis that is phenotypically similar to gliosis seen in acquired human pathologies.

Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice

“…Gliosis or astrogliosis is routinely observed in cortical tubers from individuals with TSC (34). We determined the presence of gliosis using immunostaining for glial fibrillary acidic protein (GFAP).…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…The presence of inflammatory cells/molecules [198,199] and astrogliosis [200,201] may contribute to the changes in cell morphology in tubers. Interestingly, the development of cystic changes (end-stage of degenerative changes, affecting the white matter) has been shown to be associated with a TSC2 gene mutation and with a more aggressive seizure phenotype [202,203].…”

Tuberous sclerosis and epilepsy: Role of astrocytes

“…Although many of GCs express neuroglial progenitor cell markers such as nestin (Crino et al, 1996), vinentin (Sosunov et al, 2008), and Sox2 (Orlova et al, 2010), a subpopulation of GCs express GFAP and S100 proteins (Boer et al, 2008a,b;Scheithauer and Regan, 1999), markers of astrocytic lineage, either in combination with neural marker proteins (neurofilament, internexin, neuron specific enolase, tubulin, and MAP2C) or in isolation. Thus, an unanswered question regarding the pathogenesis of tubers is whether GCs derive from glial or neuronal cell precursors during early brain development or perhaps these cells represent an intermediate phenotype.…”

“…Although it is apparent that increased numbers of astrocytes may represent a cellular reaction to surrounding changes in the neuropil, e.g., laminar disorganization and the presence of GCs, it is also possible that astrocytes are produced in greater numbers in tubers during brain development. In the only comprehensive study of astrocytes in TSC, there were marked morphological and cell biological differences between subpopulations of astrocytes in tubers (Sosunov et al, 2008). These investigators hypothesized that the development of astrogliosis in tubers was directly related to TSC1 and TSC2 mutations and played a central pathogenic role in lesion formation.…”