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      Identification of compounds with anti-convulsant properties in a zebrafish model of epileptic seizures

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          SUMMARY

          The availability of animal models of epileptic seizures provides opportunities to identify novel anticonvulsants for the treatment of people with epilepsy. We found that exposure of 2-day-old zebrafish embryos to the convulsant agent pentylenetetrazole (PTZ) rapidly induces the expression of synaptic-activity-regulated genes in the CNS, and elicited vigorous episodes of calcium (Ca 2+) flux in muscle cells as well as intense locomotor activity. We then screened a library of ∼2000 known bioactive small molecules and identified 46 compounds that suppressed PTZ-inducedtranscription of the synaptic-activity-regulated gene fos in 2-day-old (2 dpf) zebrafish embryos. Further analysis of a subset of these compounds, which included compounds with known and newly identified anticonvulsant properties, revealed that they exhibited concentration-dependent inhibition of both locomotor activity and PTZ-induced fos transcription, confirming their anticonvulsant characteristics. We conclude that this in situ hybridisation assay for fos transcription in the zebrafish embryonic CNS is a robust, high-throughput in vivo indicator of the neural response to convulsant treatment and lends itself well to chemical screening applications. Moreover, our results demonstrate that suppression of PTZ-induced fos expression provides a sensitive means of identifying compounds with anticonvulsant activities.

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          Activity-dependent regulation of inhibitory synapse development by Npas4.

          Neuronal activity regulates the development and maturation of excitatory and inhibitory synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory synapse development. However, less is known about the molecular mechanisms that regulate the activity-dependent development of GABA (gamma-aminobutyric acid)-releasing inhibitory synapses. Here we report the identification of a transcription factor, Npas4, that plays a role in the development of inhibitory synapses by regulating the expression of activity-dependent genes, which in turn control the number of GABA-releasing synapses that form on excitatory neurons. These findings demonstrate that the activity-dependent gene program regulates inhibitory synapse development, and suggest a new role for this program in controlling the homeostatic balance between synaptic excitation and inhibition.
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            Critical review of current animal models of seizures and epilepsy used in the discovery and development of new antiepileptic drugs.

            Animal models for seizures and epilepsy have played a fundamental role in advancing our understanding of basic mechanisms underlying ictogenesis and epileptogenesis and have been instrumental in the discovery and preclinical development of novel antiepileptic drugs (AEDs). However, there is growing concern that the efficacy of drug treatment of epilepsy has not substantially improved with the introduction of new AEDs, which, at least in part, may be due to the fact that the same simple screening models, i.e., the maximal electroshock seizure (MES) and s.c. pentylenetetrazole (PTZ) seizure tests, have been used as gatekeepers in AED discovery for >6 decades. It has been argued that these old models may identify only drugs that share characteristics with existing drugs, and are unlikely to have an effect on refractory epilepsies. Indeed, accumulating evidence with several novel AEDs, including levetiracetan, has shown that the MES and PTZ models do not identify all potential AEDs but instead may fail to discover compounds that have great potential efficacy but work through mechanisms not tested by these models. Awareness of the limitations of acute seizure models comes at a critical crossroad. Clearly, preclinical strategies of AED discovery and development need a conceptual shift that is moving away from using models that identify therapies for the symptomatic treatment of epilepsy to those that may be useful for identifying therapies that are more effective in the refractory population and that may ultimately lead to an effective cure in susceptible individuals by interfering with the processes underlying epilepsy. To realize this goal, the molecular mechanisms of the next generation of therapies must necessarily evolve to include targets that contribute to epileptogenesis and pharmacoresistance in relevant epilepsy models. Copyright © 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
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              Pentylenetetrazole induced changes in zebrafish behavior, neural activity and c-fos expression.

              Rodent seizure models have significantly contributed to our basic understanding of epilepsy. However, medically intractable forms of epilepsy persist and the fundamental mechanisms underlying this disease remain unclear. Here we show that seizures can be elicited in a simple vertebrate system e.g. zebrafish larvae (Danio rerio). Exposure to a common convulsant agent (pentylenetetrazole, PTZ) induced a stereotyped and concentration-dependent sequence of behavioral changes culminating in clonus-like convulsions. Extracellular recordings from fish optic tectum revealed ictal and interictal-like electrographic discharges after application of PTZ, which could be blocked by tetrodotoxin or glutamate receptor antagonists. Epileptiform discharges were suppressed by commonly used antiepileptic drugs, valproate and diazepam, in a concentration-dependent manner. Up-regulation of c-fos expression was also observed in CNS structures of zebrafish exposed to PTZ. Taken together, these results demonstrate that chemically-induced seizures in zebrafish exhibit behavioral, electrographic, and molecular changes that would be expected from a rodent seizure model. Therefore, zebrafish larvae represent a powerful new system to study the underlying basis of seizure generation, epilepsy and epileptogenesis.
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                Author and article information

                Journal
                Dis Model Mech
                Dis Model Mech
                dmm
                DMM
                Disease Models & Mechanisms
                The Company of Biologists Limited
                1754-8403
                1754-8411
                November 2012
                21 June 2012
                : 5
                : 6
                : 773-784
                Affiliations
                [1 ]MRC Centre for Developmental and Biomedical Genetics, Department of Biomedical Science, University of Sheffield, Firth Court, Western Bank, Sheffield, S10 2TN, UK
                Author notes
                [* ]Author for correspondence ( v.t.cunliffe@ 123456sheffield.ac.uk )
                Article
                0050773
                10.1242/dmm.010090
                3484860
                22730455
                e713c20b-08df-4f46-9959-b388731eb74b
                © 2012. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License ( http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

                History
                : 18 April 2012
                : 16 June 2012
                Categories
                Research Article
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                Molecular medicine
                Molecular medicine

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