Hippocampal volume and cell density changes in a mouse model of human genetic epilepsy

Abstract

Objective: The human γ-aminobutyric acid type A (GABA A)γ2R43Q (R43Q) mutation is associated with genetic epilepsy with febrile seizures. R43Qmice in the C57Bl/6J background do not display spontaneous seizures, but are significantly more susceptible to hyperthermic seizures, providing a model with enhanced seizure susceptibility without the confounding influence of ongoing epileptic activity. Because of GABA's role in brain development, we sought to determine whether the R43Q mutation alters brain structure before the appearance of seizures. Methods: We used 16.4-tesla, high-field MRI to determine the volumes of hippocampal subregions. Histologic analysis of the same brains allowed stereology-based estimates of neuron counts to be obtained in CA1-3 and the dentate gyrus. Results: Morphologic changes were evident in seizure-naive hippocampi of susceptible mice. Dentate granule cell MRI determined that volume was 5% greater in R43Q mice compared with controls (0.628 mm3, 95% confidence interval [CI] 0.611-0.645 vs 0.595 mm3, 95% CI 0.571-0.619). The dentate granule cell density was 30% higher in R43Q compared with control mice (553 × 103 cells/mm3, 95% CI 489-616 vs 427 × 103 cells/mm3, 95% CI 362-491). Conclusions: In a genetic epilepsy model that is both seizure-naive and carries an allele for febrile seizure susceptibility, we have determined hippocampal structural changes that may be applied as a biomarker for seizure susceptibility. © 2013 American Academy of Neurology.