title: Optogenetic and potassium channel gene therapy in a rodent model of focal neocortical epilepsy.
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.
authors.affiliation: UCL Institute of Neurology, London WC1N 3BG, UK.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Wykes
authors.forename: Joost H
authors.initials: JH
authors.lastname: Heeroma
authors.forename: Laura
authors.initials: L
authors.lastname: Mantoan
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Zheng
authors.forename: Douglas C
authors.initials: DC
authors.lastname: MacDonald
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
authors.forename: Kevan S
authors.initials: KS
authors.lastname: Hashemi
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schorge
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004569:Electroencephalography; D004828:Epilepsies, Partial / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D015316:Genetic Therapy; D051662:Kv1.1 Potassium Channel / Q000235:genetics* / Q000627:therapeutic use*; D016086:Lentivirus / Q000235:genetics; D008297:Male; D019579:Neocortex / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009474:Neurons / Q000473:pathology; D062308:Optogenetics; D017966:Pyramidal Cells / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013744:Tetanus Toxin / Q000008:administration & dosage
chemical_list: D013744:Tetanus Toxin; D051662:Kv1.1 Potassium Channel