Abstract
The complex pathogenesis of temporal lobe epilepsy includes neuronal and glial pathology, synaptic reorganization, and an immune response. However, the spatio-temporal pattern of structural changes in the brain that provide a substrate for seizure generation and modulate the seizure phenotype is yet to be completely elucidated. We used quantitative magnetic resonance imaging (MRI) to study structural changes triggered by status epilepticus (SE) and their association with epileptogenesis and with activation of complement component 3 (C3). SE was induced by injection of pilocarpine in CD1 mice. Quantitative diffusion-weighted imaging and T2 relaxometry was performed using a 16.4-Tesla MRI scanner at 3 h and 1, 2, 7, 14, 28, 35, and 49 days post-SE. Following longitudinal MRI examinations, spontaneous recurrent seizures and interictal spikes were quantified using continuous video-EEG monitoring. Immunohistochemical analysis of C3 expression was performed at 48 h, 7 days, and 4 months post-SE. MRI changes were dynamic, reflecting different outcomes in relation to the development of epilepsy. Apparent diffusion coefficient changes in the hippocampus at 7 days post-SE correlated with the severity of the evolving epilepsy. C3 activation was found in all stages of epileptogenesis within the areas with significant MRI changes and correlated with the severity of epileptic condition.
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Abbreviations
- TLE:
-
Temporal lobe epilepsy
- SE:
-
Status epilepticus
- C3:
-
Complement component 3
- MRI:
-
Magnetic resonance imaging
- SRS:
-
Spontaneous recurrent seizures
- DWI:
-
Diffusion-weighted imaging
- NS:
-
No seizures
- CN:
-
Control
- ADC:
-
Apparent diffusion coefficient
- T2:
-
Apparent transverse relaxation time
- CA1:
-
Cornu Ammonis 1 region of the hippocampus proper
- gcl:
-
Granule cell layer
- H:
-
Hilus of the dentate gyrus
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Acknowledgments
We would like to thank the National Imaging Facility (NIF) and the Queensland NMR Network (QNN) for access to the 16.4 T scanner and technical support. We thank Australian Mouse Brain Mapping Consortium for providing an atlas for image registration. We express our gratitude to Dr. Karin Borges for advice in establishing a mouse pilocarpine model, and to Mr. Luke Hammond and Ms Jane Ellis from Queensland Brain Institute for technical advice and assistance. This project was funded by the National Health and Medical Research Council (NHMRC) of Australia (to D.C.R) and the University of Queensland New Staff Research Start Up Grant (to I.K.).
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429_2013_528_MOESM1_ESM.tif
Supplementary figure 1 Receiver observed curves (ROC) for ADC changes in the ventral hippocampus assessed at 7 days after status epilepticus, which predicted severity of epileptic condition (i.e. increase in spike frequency) in the chronic stage. The area under the curve (AUC) for ROC curve is 0.93 indicating high predictive accuracy of ADC values (TIFF 10974 kb)
429_2013_528_MOESM2_ESM.tif
Supplementary figure 2 Distribution of GFAP (A1, B1, C1) and C3 (A2, B2, C2) immunoreactivity in the septal hippocampus 3 months after pilocarpine-induced status epilepticus in the 3 SE mice with interictal spiking on EEG but no spontaneous seizures. Note reactive astrogliosis and prominent increased expression of C3 in astrocytes in the hilus and granule cell layer of the dentate gyrus, as well as ablation of CA1 in animals #20 and #37. Animal #66 did not demonstrate severe astrogliosis or hippocampal atrophy, but had increased levels of C3 expression in astrocytes forming continuous band in the subgranular zone. Scale bar in all panels 100µm (TIFF 10196 kb)
429_2013_528_MOESM3_ESM.tif
Supplementary figure 3 Volumetric MRI data and a ROI-based analysis of the dynamics of hippocampal ADC and T2 changes in the animals with spikes + SRS and those with spikes only. The quantitative data from individual animals are presented as scatterplots. Closed circles refer to animals with spontaneous recurrent seizures and open circles to 3 animals with spikes only. Animals in Group 1 were imaged at 3 hours and 7, 28 and 49 days after pilocarpine injection and in Group II at 1, 2, 14 and 35 days after pilocarpine injection. The results show that the 2 animals with more severe hippocampal sclerosis observed in histological sections (#20, #37, Group 1) had more severe hippocampal damage on MRI, and the third animal (#66, Group 2, D-F) had less severe damage compared to the group of animals with SRS. Severity of hippocampal damage is reflected by a decrease in relative hippocampal volumes (A) and gradual increase in the hippocampal ADC and T2 values during follow-up time (B,C), above the group mean from animals with SRS (TIFF 17536 kb)
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Kharatishvili, I., Shan, Z.Y., She, D.T. et al. MRI changes and complement activation correlate with epileptogenicity in a mouse model of temporal lobe epilepsy. Brain Struct Funct 219, 683–706 (2014). https://doi.org/10.1007/s00429-013-0528-4
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DOI: https://doi.org/10.1007/s00429-013-0528-4