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      Advantages of Repeated Low Dose against Single High Dose of Kainate in C57BL/6J Mouse Model of Status Epilepticus: Behavioral and Electroencephalographic Studies


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          A refined kainate (KA) C57BL/6J mouse model of status epilepticus (SE) using a repeated low dose (RLD) of KA (5 mg/kg, intraperitoneal; at 30 min intervals) was compared with the established single high dose (SHD) of KA (20 mg/kg, intraperitoneal) model. In the RLD group, increased duration of convulsive motor seizures (CMS, Racine scale stage ≥3) with a significant reduction in mortality from 21% to 6% and decreased variability in seizure severity between animals/batches were observed when compared to the SHD group. There was a significant increase in the percentage of animals that reached stage-5 seizures (65% versus 96%) in the RLD group. Integrated real-time video-EEG analysis of both groups, using NeuroScore software, revealed stage-specific spikes and power spectral density characteristics. When the seizures progressed from non-convulsive seizures (NCS, stage 1–2) to CMS (stage 3–5), the delta power decreased which was followed by an increase in gamma and beta power. A transient increase in alpha and sigma power marked the transition from NCS to CMS with characteristic ‘high frequency trigger’ spikes on the EEG, which had no behavioral expression. During SE the spike rate was higher in the RLD group than in the SHD group. Overall these results confirm that RLD of KA is a more robust and consistent mouse model of SE than the SHD of KA mouse model.

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          The kainic acid model of temporal lobe epilepsy.

          The kainic acid model of temporal lobe epilepsy has greatly contributed to the understanding of the molecular, cellular and pharmacological mechanisms underlying epileptogenesis and ictogenesis. This model presents with neuropathological and electroencephalographic features that are seen in patients with temporal lobe epilepsy. It is also characterized by a latent period that follows the initial precipitating injury (i.e., status epilepticus) until the appearance of recurrent seizures, as observed in the human condition. Finally, the kainic acid model can be reproduced in a variety of species using either systemic, intrahippocampal or intra-amygdaloid administrations. In this review, we describe the various methodological procedures and evaluate their differences with respect to the behavioral, electroencephalographic and neuropathological correlates. In addition, we compare the kainic acid model with other animal models of temporal lobe epilepsy such as the pilocarpine and the kindling model. We conclude that the kainic acid model is a reliable tool for understanding temporal lobe epilepsy, provided that the differences existing between methodological procedures are taken into account. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Kindling and status epilepticus models of epilepsy: rewiring the brain.

            This review focuses on the remodeling of brain circuitry associated with epilepsy, particularly in excitatory glutamate and inhibitory GABA systems, including alterations in synaptic efficacy, growth of new connections, and loss of existing connections. From recent studies on the kindling and status epilepticus models, which have been used most extensively to investigate temporal lobe epilepsy, it is now clear that the brain reorganizes itself in response to excess neural activation, such as seizure activity. The contributing factors to this reorganization include activation of glutamate receptors, second messengers, immediate early genes, transcription factors, neurotrophic factors, axon guidance molecules, protein synthesis, neurogenesis, and synaptogenesis. Some of the resulting changes may, in turn, contribute to the permanent alterations in seizure susceptibility. There is increasing evidence that neurogenesis and synaptogenesis can appear not only in the mossy fiber pathway in the hippocampus but also in other limbic structures. Neuronal loss, induced by prolonged seizure activity, may also contribute to circuit restructuring, particularly in the status epilepticus model. However, it is unlikely that any one structure, plastic system, neurotrophin, or downstream effector pathway is uniquely critical for epileptogenesis. The sensitivity of neural systems to the modulation of inhibition makes a disinhibition hypothesis compelling for both the triggering stage of the epileptic response and the long-term changes that promote the epileptic state. Loss of selective types of interneurons, alteration of GABA receptor configuration, and/or decrease in dendritic inhibition could contribute to the development of spontaneous seizures.
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              Behavioral phenotyping of transgenic and knockout mice: experimental design and evaluation of general health, sensory functions, motor abilities, and specific behavioral tests.

              J Crawley (1999)
              Rigorous experimental design can minimize the high risk of false positives and false negatives in the behavioral phenotyping of a new transgenic or knockout mouse. Use of well established, quantitative, reproducible behavioral tasks, appropriate Ns, correct statistical methods, consideration of background genes contributed by the parental strains, and attention to litter and gender issues, will maximize meaningful comparisons of -/-, +/-, and +/+ genotypes. Strategies developed and used by our laboratory are described in this review. Preliminary observations evaluate general health and neurological reflexes. Sensory abilities and motor functions are extensively quantitated. Specific tests include observations of home cage behaviors, body weight, body temperature, appearance of the fur and whiskers, righting reflex, acoustic startle, eye blink, pupil constriction, vibrissae reflex, pinna reflex, Digiscan open field locomotion, rotarod motor coordination, hanging wire, footprint pathway, visual cliff, auditory threshold, pain threshold, and olfactory acuity. Hypothesis testing then focuses on at least three well-validated tasks within each relevant behavioral domain. Specific tests for mice are described herein for the domains of learning and memory, feeding, nociception, and behaviors relevant to discrete symptoms of human anxiety, depression, schizophrenia, and drug addiction. An example of our approach is illustrated in the behavioral phenotyping of C/EBPdelta knockout mice, which appear to be normal on general health, neurological reflexes, sensory and motor tasks, and the Morris water task, but show remarkably enhanced performance on contextual fear conditioning. Copyright 1999 Elsevier Science B.V.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                6 May 2014
                : 9
                : 5
                : e96622
                [1 ]Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
                [2 ]Department of Biomedical Science, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America
                [3 ]Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
                University G. D'Annunzio, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TT. Performed the experiments: KT SP EB. Analyzed the data: KT SP EB. Wrote the paper: TT SP. Secured funding: TT. Recruited and trained personnel: TT. Proofread the first and the second drafts of the manuscript: GS.

                Copyright @ 2014

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                : 18 December 2013
                : 9 April 2014
                Page count
                Pages: 12
                Funding for EB and KT was from Biotechnology 436 and Biological Sciences Research Council, UK and the University of Liverpool, UK through TT as PI during his appointment in the University of Liverpool until 31 October 2012. SP was supported by TT's start-up fund from the Iowa State University, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Research Article
                Biology and Life Sciences
                Behavioral Neuroscience
                Medicine and Health Sciences
                Diagnostic Medicine
                Clinical Neurophysiology
                Epileptic Seizures
                Absence Seizures
                Status Epilepticus
                Temporal Lobe Epilepsy
                Research and Analysis Methods
                Model Organisms
                Animal Models
                Mouse Models



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