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Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.

Wykes, RC; Heeroma, JH; Mantoan, L; Zheng, K; Macdonald, DC; Deisseroth, K; Hashemi, KS; ... Kullmann, DM; + view all (2012) Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy. Science Translational Medicine , 4 (161) , Article 161ra152. 10.1126/scitranslmed.3004190. Green open access

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Abstract

Neocortical epilepsy is frequently drug-resistant. Surgery to remove the epileptogenic zone is only feasible in a minority of cases, leaving many patients without an effective treatment. We report the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model in which epilepsy is induced by tetanus toxin injection in the motor cortex. By applying several complementary methods that use continuous wireless electroencephalographic monitoring to quantify epileptic activity, we observed increases in high frequency activity and in the occurrence of epileptiform events. Pyramidal neurons in the epileptic focus showed enhanced intrinsic excitability consistent with seizure generation. Optogenetic inhibition of a subset of principal neurons transduced with halorhodopsin targeted to the epileptic focus by lentiviral delivery was sufficient to attenuate electroencephalographic seizures. Local lentiviral overexpression of the potassium channel Kv1.1 reduced the intrinsic excitability of transduced pyramidal neurons. Coinjection of this Kv1.1 lentivirus with tetanus toxin fully prevented the occurrence of electroencephalographic seizures. Finally, administration of the Kv1.1 lentivirus to an established epileptic focus progressively suppressed epileptic activity over several weeks without detectable behavioral side effects. Thus, gene therapy in a rodent model can be used to suppress seizures acutely, prevent their occurrence after an epileptogenic stimulus, and successfully treat established focal epilepsy.

Type: Article
Title: Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.3004190
Publisher version: http://stm.sciencemag.org/cgi/content/full/4/161/1...
Language: English
Additional information: Permission to access this article has been granted by AAAS for personal use only. The abstract, reprint and full text can be found via the following links. Abstract: http://stm.sciencemag.org/cgi/content/abstract/4/161/161ra152?ijkey=vICwUAhuPUqVk&keytype=ref&siteid=scitransmed; Reprint: http://stm.sciencemag.org/cgi/rapidpdf/4/161/161ra152?ijkey=vICwUAhuPUqVk&keytype=ref&siteid=scitransmed; Full Text: http://stm.sciencemag.org/cgi/content/full/4/161/161ra152?ijkey=vICwUAhuPUqVk&keytype=ref&siteid=scitransmed;
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: http://discovery.ucl.ac.uk/id/eprint/1369973
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