TY - JOUR
T1 - Hippocampal volume and cell density changes in a mouse model of human genetic epilepsy
AU - Richards, Kay L.
AU - Kurniawan, Nyoman D.
AU - Yang, Zhengyi
AU - Kim, Tae Hwan
AU - Keller, Marianne D.
AU - Low, Jun
AU - Ullmann, Jeremy F.P.
AU - Cole, Stacey
AU - Foong, Samuel
AU - Galloway, Graham J.
AU - Reid, Christopher A.
AU - Paxinos, George
AU - Reutens, David C.
AU - Petrou, Steven
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/3/26
Y1 - 2013/3/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84876225984&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e31828970ec
DO - 10.1212/WNL.0b013e31828970ec
M3 - Article
C2 - 23468543
AN - SCOPUS:84876225984
VL - 80
SP - 1240
EP - 1246
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 13
ER -