Abstracts

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disease caused by mutations in TSC genes that encode hamartin (TSC1) and tuberin (TSC2). These proteins affect cellular migration, proliferation, and differentiation in multiple organs, including the brain. In particular, it has been suggested that these proteins may represent growth suppressors. Epilepsy is one of the major complications of TSC and affects about 85% of patients. TSC shares histopathologic similarities with severe forms of focal cortical dysplasia (CD), specifically the presence of cytomegalic neurons and balloon cells., In this study we examined the morphological and electrophysiological properties of cells in cortical tissue samples from pediatric cases with TSC (n=11, ages 1.8-10.1 yr) or severe CD (n=15, ages 0.2-14 yr), that underwent surgery for the treatment of pharmacoresistant epilepsy. Normal- and abnormal-appearing cells in slices were identified morphologically by infrared videomicroscopy and biocytin labeling (n=72 in TSC and n=151 in severe CD). Electrophysiological membrane properties were assessed with whole-cell patch clamp recordings in current and voltage clamp modes., In both TSC and severe CD cases, abnormal-appearing cells were observed in the cortical mantle and classified into four principal groups. The first consisted of very large, pyramidal-shaped cells corresponding to cytomegalic neurons. The second group included large, non-pyramidal cells with atypical somatodendritic morphology that correspond to balloon cells. The third group included misoriented and dysmorphic pyramidal neurons, and the fourth consisted of immature-looking pyramidal cells. Morphologically, abnormal cells from TSC and severe CD cases were very similar. Electrophysiologically, the most abnormal properties were found in cytomegalic neurons and balloon cells. Cytomegalic neurons were hyperexcitable, whereas balloon cells had no active inward currents and lacked synaptic inputs. Balloon cells were found more frequently in TSC cases, whereas cytomegalic pyramidal neurons occurred more frequently in severe CD cases., Besides the frequency of occurrence, there were no clear morphological or electrophysiological differences in cytomegalic neurons and balloon cells from TSC and CD patients, suggesting a link between the lesions produced by TSC gene mutations and the cellular alterations observed in severe forms of CD., (Supported by NIH NS38992.)