[Frontiers in Bioscience, Elite, 8, 390-411, June 1, 2016]

Immediate epileptogenesis: Impact on brain in C57BL/6J mouse kainate model

Sreekanth Puttachary 1 , Shaunik Sharma 1 , Achala Thippeswamy 1 , Thimmasettappa Thippeswamy 1

1Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames IA 50011-1250, USA

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Materials and methods
    3.1. Animal source and ethics statement
    3.2. Chemicals and reagents
    3.3. Mild and severe SE induction with kainate and the experimental groups
        3.3.1. Cortical EEG acquisition with continuous video EEG monitoring and analysis
    3.4. Morris Water Maze test and quantification
        3.4.1. Fixed platform cue learning in Morris water maze
        3.4.2. Training
        3.4.3. Probe trial
    3.5. MRI and quantification
    3.6. Tissue processing for histology and IHC
        3.6.1. Immunopositive cell quantification
    3.7. Statistics
4. Results
    4.1. The epileptiform spike rate and the frequency of spontaneous CS increase with the severity of SE during the first two weeks after the SE
    4.2. Electrographic features of epileptogenesis: Characteristics of post-diazepam EEG, pre-, post-, and inter-ictal spikes, and NCS clusters during the first two weeks of post-SE
    4.3. Impact of epileptiform spiking and spontaneous CS on brain pathology at 7, 14 and 28 day post-SE
    4.4. Impact of epileptiform spiking, spontaneous CS and electrographic NCS, and brain pathology on hippocampal dependent discriminatory learning and memory
5. Discussion
6. Acknowledgement
7. References

1. ABSTRACT

We have recently demonstrated immediate epileptogenesis in the C57BL/6J mouse, the strain that is resistant to kainate-induced neurotoxicity. By using a repeated low dose of kainate, we produced mild and severe status epilepticus (SE) models. In the present study, we demonstrate the impact of mild and severe SE, and spontaneous convulsive/nonconvulsive seizures (CS/NCS) on structure and function of the hippocampus, entorhinal cortex, and amygdala at 7, 14 and 28 day post-SE. Immunohistochemistry (IHC) of brain sections confirmed reactive astrogliosis and microgliosis, neurodegeneration, and increased neurogenesis in both groups. The epileptiform spike rate was higher in the severe group during first 12 days, but they decreased thereafter. Morris water maze test confirmed cognitive deficit in both mild and severe groups at 12d post-SE. However, MRI and IHC at 18 weeks did not reveal any changes in the hippocampus. These findings suggest that in C57BL/6J mice, immediate spontaneous CS could be responsible for early brain pathology or vice versa, however, the persistent spontaneous NCS for a long-term had no impact on the brain structure in both groups.

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88. A. R. Brooks-Kayal, K. G. Bath, A. T. Berg, A. S. Galanopoulou, G. L. Holmes, F. E. Jensen, A. M. Kanner, T. J. O’Brien, V. H. Whittemore, M. R. Winawer, M. Patel and H. E. Scharfman: Issues related to symptomatic and disease-modifying treatments affecting cognitive and neuropsychiatric comorbidities of epilepsy. Epilepsia, 54 Suppl 4, 44-60 (2013)
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89. J. K. Kleen, R. C. Scott, G. L. Holmes, D. W. Roberts, M. M. Rundle, M. Testorf, P. P. Lenck-Santini and B. C. Jobst: Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology, 81(1), 18-24 (2013)
DOI: 10.1212/WNL.0b013e318297ee50

90. G. L. Holmes: EEG abnormalities as a biomarker for cognitive comorbidities in pharmacoresistant epilepsy. Epilepsia, 54 Suppl 2, 60-2 (2013)
DOI: 10.1111/epi.12186

91. G. L. Holmes: Cognitive impairment in epilepsy: the role of network abnormalities. Epileptic Disord, 17(2), 101-16 (2015)

Key Words: Epileptogenesis, Gliosis, Neurodegeneration, Neurogenesis, Cognitive Deficits

Send correspondence to: Thimmasettappa Thippeswamy, Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames IA 50011-1250, USA, Tel: 515-294-2571, Fax: 515-294-2315 E-mail: tswamy@iastate.edu