Background EEG Connectivity Captures the Time-Course of Epileptogenesis in a Mouse Model of Epilepsy
Piotr SłowińskiLaurent SheybaniChristoph M. MichelMark P. RichardsonCharles QuairiauxJohn R. TerryMarc Goodfellow
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Large-scale brain networks are increasingly recognized as important for the generation of seizures in epilepsy. However, how a network evolves from a healthy state through the process of epileptogenesis remains unclear. To address this question, here, we study longitudinal epicranial background EEG recordings (30 electrodes, EEG free from epileptiform activity) of a mouse model of mesial temporal lobe epilepsy. We analyze functional connectivity networks and observe that over the time course of epileptogenesis the networks become increasingly asymmetric. Furthermore, computational modelling reveals that a set of nodes, located outside of the region of initial insult, emerges as particularly important for the network dynamics. These findings are consistent with experimental observations, thus demonstrating that ictogenic mechanisms can be revealed on the EEG, that computational models can be used to monitor unfolding epileptogenesis and that both the primary focus and epileptic network play a role in epileptogenesis.Epilepsy, a neurological disorder affecting over 50 million individuals globally, is characterized by an enduring predisposition and diverse consequences, both neurobiological and social. Acquired epilepsy, constituting 30% of cases, often results from brain-damaging injuries like ischemic stroke. With one third of epilepsy cases being resistant to existing drugs and without any preventive therapeutics for epileptogenesis, identifying anti-epileptogenic targets is crucial. Stroke being a leading cause of acquired epilepsy, particularly in the elderly, prompts the need for understanding post-stroke epileptogenesis. Despite the challenges in studying stroke-evoked epilepsy in rodents due to poor long-term survival rates, in this presented study the use of an animal care protocol allowed for comprehensive investigation. We highlight the role of matrix metalloproteinase-9 (MMP-9) in post-stroke epileptogenesis, emphasizing MMP-9 involvement in mouse models and its potential as a therapeutic target. Using a focal Middle Cerebral Artery occlusion model, this study demonstrates MMP-9 activation following ischemia, influencing susceptibility to seizures. MMP-9 knockout reduces epileptic features, while overexpression exacerbates them. The findings show that MMP-9 is a key player in post-stroke epileptogenesis, presenting opportunities for future therapies and expanding our understanding of acquired epilepsy.
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This study reviews the different in vivo experimental models that have been used for the study of epileptogenesis. In this review we will focus on how to replicate the different models that have led to the study of partial seizures, as well as generalized seizures and the status epilepticus. The main characteristics that participate in the processes that generate and modulate the manifestations of different models of epileptogenesis are described. The development of several models of experimental epilepsy in animals has clearly helped the study of specific brain areas capable of causing convulsions. The experimental models of epilepsy also have helped in the study the mechanisms and actions of epilepsy drugs. In order to develop experimental animal models of epilepsy, animals are generally chosen according to the kind of epilepsy that can be developed and studied. It is currently known that animal species can have epileptic seizures similar to those in humans. However, it is important to keep in mind that it has not been possible to entirely evaluate all manifestations of human epilepsy. Notwithstanding, these experimental models of epilepsy have allowed a partial understanding of most of the underlying mechanisms of this disease. Keywords: Epilepsy models, aluminum hydroxide, kainic acid, kindling, electroshock seizure, penicillin, bicuculline, GABA, tetanic toxin, pilocarpine, epileptogenesis, epilepticus, glutamenergic neurotransmission, epileptic seizures, Papio papio baboon model, epileptogenic, cerebral cortex (Cx), sensorimotor cortex, glutamate decarboxylase (GAD), electroencephalogram (EEG), GABAergic neurons, zinc sulphate, amygdala (Am), electroencephalographic, Glutamate, hippocampal CA1, antiepileptic drugs, neocortex, Pentylentetrazol, axonal growth, Carbamazepine, mesencephalus, glutaminergic synapses, intraperitoneal, intracortical, Bicuculine, neurotransmitter, inferior colliculi, stroboscopic stimulation, cerebral hemispheres, barbiturates, Pilocarpine hydrochloride, amygdaloid, thalamus, pilocarpine-treated animals, electroshock model, alumina cream model, electroencephalographic activity
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Epilepsy syndromes
Idiopathic generalized epilepsy
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Abstract Epilepsy frequently develops as a result of brain insult; however, there are no tools allowing to predict which patients suffering from trauma will eventually develop epilepsy. microRNAs are interesting candidates for biomarkers, as several of them have been described to change their levels in the brains, and in the plasma of epileptic subjects. This study was conducted to evaluate the usefulness of plasma miRNAs as epileptogenesis/epilepsy biomarkers. In our studies, we used a rat model of temporal lobe epilepsy. An epileptogenic insult was status epilepticus evoked by stimulation of the left lateral nucleus of the amygdala. Next, animals were continuously video and EEG monitored for 3 months. Blood was collected at 14, 30, 60, and 90 days after stimulation. Blood plasma was separated and miRNA levels were analyzed. We compared miRNA levels between sham-operated and stimulated animals, and between animals with high and low numbers of seizures. We propose three miRNAs that could be biomarkers of epilepsy: miR-671, miR-9a-3p and miR-7a-5p. According to us, miR-206-5p is a potential biomarker of epileptogenesis, and miR-221-3p is a potential biomarker of epilepsy severity. We think that these five miRNAs can be considered in the future as potential treatment targets.
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