Irradiation exacerbates cortical cytopathology in the Eker rat model of tuberous sclerosis complex, but does not induce hyperexcitability.

ABSTRACT

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by multi-organ pathologies. Most TSC patients exhibit seizures, usually starting in early childhood. The neuropathological hallmarks of the disease - cortical tubers, containing cytopathological neuronal and glial cell types - appear to be the source of seizure initiation. However, the contribution of these aberrant cell populations to TSC-associated epilepsies is not fully understood. To gain further insight, investigators have attempted to generate animal models with TSC-like brain abnormalities. In the current study, we focused on the Eker rat, in which there is a spontaneous mutation of the TSC2 gene (TSC2+/-). We attempted to exacerbate TSC-like brain pathologies with a "second-hit" strategy - exposing young pups to ionizing irradiation of different intensities, and at different developmental timepoints (between E18 and P6). We found that the frequency of occurrence of dysmorphic neurons and giant astrocytes was strongly dependent on irradiation dose, and weakly dependent on timing of irradiation in Eker rats, but not in irradiated normal controls. The frequency of TSC-like pathology was progressive; there were many more abnormal cells at 3 months compared to 1 month post-irradiation. Measures of seizure propensity (flurothyl seizure latency) and brain excitability (paired-pulse and post-tetanic stimulation studies in vitro), however, showed no functional changes associated with the appearance of TSC-like cellular abnormalities in irradiated Eker rats.