Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis.
Tuberous sclerosis (TSC) is an autosomal dominant disorder, caused by mutations of either the TSC1 or TSC2 gene. Characteristic brain pathologies (including cortical tubers and subependymal hamartomas/giant astrocytomas) are thought to cause epilepsy, as well as other neurological dysfunction. The Eker rat, which carries a spontaneous germline mutation of the TSC2 gene (TSC2+/-), provides a unique animal model in which to study the relationship between TSC cortical pathologies and epilepsy. In the present study, we have analyzed the seizure propensity and histopathological features of a modified Eker rat preparation, in which early postnatal irradiation was employed as a "second hit" stimulus in an attempt to exacerbate cortical malformations and increase seizure propensity. Irradiated Eker rats had a tendency toward lower seizure thresholds (latencies to flurothyl-induced seizures) than seen in non-irradiated Eker rats (significant difference) or irradiated wild-type rats (non-significant difference). The majority of irradiated Eker rats exhibited dysplastic cytomegalic neurons and giant astrocyte-like cells, similar to cytopathologies observed in TSC lesions of patients. The most prominent features in these brains were hamartoma-like lesions involving large eosinophilic cells, similar to giant tuber cells in human TSC. In some cells from these hamartomas, immunocytochemistry revealed features of both neuronal and glial phenotypes, suggesting an undifferentiated or immature cell population. Both normal-appearing and dysmorphic neurons, as well as cells in the hamartomas, exhibited immunopositivity for tuberin, the protein product of the TSC2 gene.
Wenzel
H Jürgen
HJ
Department of Neurological Surgery, University of California at Davis, 1 Shields Avenue, Davis, CA 95616, USA. hjwenzel@ucdavis.edu
Patel
Leena S
LS
Robbins
Carol A
CA
Emmi
Adriana
A
Yeung
Raymond S
RS
Schwartzkroin
Philip A
PA
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005481:Flurothyl; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011922:Rats, Mutant Strains; D011930:Reaction Time / Q000528:radiation effects; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013194:Staining and Labeling; D014402:Tuberous Sclerosis / Q000378:metabolism* / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D014916:Whole-Body Irradiation / Q000379:methods
D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D007527:Isoenzymes; D008869:Microtubule-Associated Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577486:Nes protein, rat; D064231:Nestin; D016900:Neurofilament Proteins; D012097:Repressor Proteins; C000624653:TSC2 protein, human; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D005481:Flurothyl; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase