Characterising seizure development, behavioural comorbidities and neuroinflammation in a self-sustained electrical status epilepticus model of mesial temporal lobe epilepsy in C57BL/6J mice

Peravina Thergarajan; Matthew R. Hudson; Irena Carmichael; Jérôme Clasadonte; Stefanie Dedeurwaerdere; Terence J. O'Brien; Nigel C. Jones; Idrish Ali

Neurobiology of Disease (Jun 2022)

Characterising seizure development, behavioural comorbidities and neuroinflammation in a self-sustained electrical status epilepticus model of mesial temporal lobe epilepsy in C57BL/6J mice

Peravina Thergarajan,
Matthew R. Hudson,
Irena Carmichael,
Jérôme Clasadonte,
Stefanie Dedeurwaerdere,
Terence J. O'Brien,
Nigel C. Jones,
Idrish Ali

Affiliations

Peravina Thergarajan: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University, Department of Neurology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
Matthew R. Hudson: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University, Department of Neurology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
Irena Carmichael: Monash Micro Imaging, Central Clinical School, Melbourne, Victoria 3004, Australia
Jérôme Clasadonte: Neurosciences Therapeutic Area, UCB Pharma, Braine l'Alleud, Belgium
Stefanie Dedeurwaerdere: Neurosciences Therapeutic Area, UCB Pharma, Braine l'Alleud, Belgium; Laboratory of Experimental Haematology, University of Antwerp, Antwerp, Belgium
Terence J. O'Brien: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University, Department of Neurology, The Alfred Hospital, Melbourne, Victoria 3004, Australia
Nigel C. Jones: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University, Department of Neurology, The Alfred Hospital, Melbourne, Victoria 3004, Australia; Corresponding authors at: Department of Neurosciences, Central Clinical School, Monash University, 99, Commercial Road, Melbourne, Australia.
Idrish Ali: Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Melbourne Brain Centre, Parkville, Victoria 3050, Australia; Department of Neuroscience, Central Clinical School, Monash University, Department of Neurology, The Alfred Hospital, Melbourne, Victoria 3004, Australia; Corresponding authors at: Department of Neurosciences, Central Clinical School, Monash University, 99, Commercial Road, Melbourne, Australia.

Journal volume & issue: Vol. 168
p. 105688

Abstract

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Objective: Status epilepticus (SE) models in rodents are commonly used to research mesial temporal lobe epilepsy (mTLE) in translational epilepsy research. However, due to differences in susceptibility of mice strains to chemoconvulsants, developing this model in mice is challenging. Mice offer experimental advantages; in particular, the ability to use transgenic strains could provide novel insights about neurobiological mechanisms or ease of genetic modification to test potential therapeutic targets. This study aimed to characterise the neuroinflammation, epileptic seizures and behavioural comorbidities after self-sustained Electrical Status Epilepticus (SSSE) in C57BL/6J mice. Methods: SSSE was induced in C57BL/6J mice via prolonged electrical stimulation through a bipolar electrode implanted in the ventral hippocampus. Video electroencephalography (vEEG) monitoring was then performed between 1st month (acute timepoint) and 4th month (chronic timepoint). Brain tissues were collected at two timepoints for gene expression and immunohistochemical analysis: 7-days and 16-weeks post-SE. Additionally, at the chronic timepoint, animals underwent a series of neurobehavioural tests. Results: Sixty percent of animals that underwent SSSE developed spontaneous seizures within the first month, and an additional 25% developed seizures at the chronic timepoint. The number of seizures per week during the chronic period ranged from 0.2 to 15.7. Mortality rate was ~9% during or after SSSE. SSSE animals displayed significant spatial memory impairment and depression-like behaviour compared to sham animals. mRNA expression of inflammatory cytokines was upregulated at 7-days following SE, but equal to sham levels at 16-weeks. Significance: This study provides evidence that SSSE in C57BL/6J mice induces epileptic seizures consistent with those seen in patients with mTLE, along with cognitive and behavioural comorbidities. This model therefore has the potential to be used experimentally to uncover mechanisms to target against epileptogenesis, or to test novel treatment approaches.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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