Abstracts

Prominent astrogliosis is a typical feature of cortical tubers in Tuberous Sclerosis Complex (TSC). The relationship of these changes to mTOR activation, and the characteristics of tuberous astrogliosis in comparison to astrocytic changes in other human epilepsies have not been investigated., Neocortical and hippocampal specimens obtained during surgery on pharmaco-resistent MTLE (46 cases) and tuberous sclerosis complex (12 cases) were studied with immunohistochemistry., Most tuber astrocytes reveal high similarity to fibrous-like astrocytes seen in areas of sclerosis in MTLE. These astrocytes differ drastically from protoplasmic astrocytes found in cortex surrounding tubers in TSC and in control human neorcortex or lateral neocortex in cases of human MTLE. Morphological and immunohistochemical analysis of sclerotic and tuber astrocytes revealed that they are both characterized by increased GFAP expression and length of cell processes, accompanied by decreased expression of glutamine synthetase and astrocyte-specific glutamate transport proteins.
A subpopulation of astrocytes in tubers reveal upregulation of mTOR pathway, based on immunostaining for phospho-p70S6kinase, phospho-S6, phospho-STAT3, and phospho-4E-BP1. This mTOR activation is similar to that previously shown in giant cells (Baybis et al., 2004; Miyata et al., 2004). Acutely reactive astrocytes observed in surgically resected brain tissue from MLTE patients also revealed immunostaining for downstream components of the mTOR cascade., Two types of astrrocytes are found in human tubers: 1) mTOR activated cells similar to acutely reactive human astrocytes; 2) Sclerotic/gliotic astrocytes similar to human astrocytes in areas of sclerosis in MTLE. We hypothesize that activation of the mTOR pathway in tuber astrocytes due to TSC1 or TSC1 genes mutations leads to stepwise phenotypic transformation of astrocytes from reactive to sclerotic/gliotic cells. TSC may thus represent a genetic model of human astrogliosis found in other pathologies such as MTLE, stroke, and head trauma. The possible molecular mechanisms linking mTOR pathway activation, GFAP overproduction, and the appearance of fibrous-like astrocytes are being investigated., (Supported by Parents Against Childhood Epilepsy, NIH R21 NS 42334.)