title: Chemical-genetic attenuation of focal neocortical seizures.
abstract: Focal epilepsy is commonly pharmacoresistant, and resective surgery is often contraindicated by proximity to eloquent cortex. Many patients have no effective treatment options. Gene therapy allows cell-type specific inhibition of neuronal excitability, but on-demand seizure suppression has only been achieved with optogenetics, which requires invasive light delivery. Here we test a combined chemical-genetic approach to achieve localized suppression of neuronal excitability in a seizure focus, using viral expression of the modified muscarinic receptor hM4Di. hM4Di has no effect in the absence of its selective, normally inactive and orally bioavailable agonist clozapine-N-oxide (CNO). Systemic administration of CNO suppresses focal seizures evoked by two different chemoconvulsants, pilocarpine and picrotoxin. CNO also has a robust anti-seizure effect in a chronic model of focal neocortical epilepsy. Chemical-genetic seizure attenuation holds promise as a novel approach to treat intractable focal epilepsy while minimizing disruption of normal circuit function in untransduced brain regions or in the absence of the specific ligand.
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kätzel
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nicholson
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schorge
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.affiliation: Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Dimitri M
authors.initials: DM
authors.lastname: Kullmann
mesh_terms: D000208:Acute Disease; D000818:Animals; D003024:Clozapine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004828:Epilepsies, Partial / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D020868:Gene Silencing; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D009043:Motor Activity; D019579:Neocortex / Q000473:pathology* / Q000503:physiopathology; D010852:Picrotoxin; D010862:Pilocarpine; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4 / Q000235:genetics / Q000627:therapeutic use; D009435:Synaptic Transmission
chemical_list: D003024:Clozapine; D010852:Picrotoxin; D010862:Pilocarpine; D043588:Receptor, Muscarinic M4; C079149:clozapine N-oxide