Morphology of cerebral lesions in the Eker rat model of tuberous sclerosis

Abstract

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.

Epilepsy surgery and tuberous sclerosis complex: special considerations

“…63 The Eker rat, which carries a spontaneous heterozygous mutation of the TSC2 gene, shows mild cortical pathology but does not develop spontaneous seizures. 76 In addition, manipulation of the TSC1 and TSC2 genes in rodents has not led to tuber formation. Homozygous knockout mutations of TSC1 or TSC2 are embryonic lethal, and mice heterozygous for TSC1 or TSC2 do not develop tubers or spontaneous seizures.…”

“…Homozygous knockout mutations of TSC1 or TSC2 are embryonic lethal, and mice heterozygous for TSC1 or TSC2 do not develop tubers or spontaneous seizures. 48,76 Conditional TSC1 knockout in mouse astrocytes leads to seizures and hippocampal disorganization. 67 Disruption of TSC1 expression in neurons leads to spontaneous seizures as well as ectopic, enlarged neurons resembling giant cells.…”

Tuberous sclerosis and epilepsy: Role of astrocytes

“…In the spontaneous Tsc2 mutant Eker rat model of TSC, abnormal cytomegalic cells immunoreactive for GFAP, vimentin, and nestin were detected in deep cortical layers or along the white matter (Takahashi et al, 2004) that become more prominent following postnatal irradiation (Wenzel et al, 2004). Numerous astrocytes are present in the brains of the Tsc1 GFAP cre mouse (Uhlmann et al, 2002), and a recent study demonstrated that the brains of Tsc1…”

A Mouse Model of Tuberous Sclerosis: Neuronal Loss of Tsc1 Causes Dysplastic and Ectopic Neurons, Reduced Myelination, Seizure Activity, and Limited Survival

“…The Eker rat arose as a spontaneous inactivating mutation in Tsc2 and has been shown to develop approximately one brain hamartoma per rat (Yeung et al, 1997;Wenzel et al, 2004). These lesions have some resemblance to the brain lesions occurring in TSC, but there is no associated clinical phenotype.…”