Chemical-genetic attenuation of focal neocortical seizures

Nat Commun. 2014 May 27;5:3847. doi: 10.1038/ncomms4847.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • Clozapine / analogs & derivatives
  • Clozapine / therapeutic use
  • Epilepsies, Partial / drug therapy*
  • Epilepsies, Partial / genetics*
  • Epilepsies, Partial / physiopathology
  • Gene Silencing
  • Genetic Therapy*
  • Humans
  • Male
  • Motor Activity
  • Neocortex / pathology*
  • Neocortex / physiopathology
  • Picrotoxin
  • Pilocarpine
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M4 / genetics
  • Receptor, Muscarinic M4 / therapeutic use
  • Synaptic Transmission

Substances

  • Receptor, Muscarinic M4
  • Pilocarpine
  • Picrotoxin
  • Clozapine
  • clozapine N-oxide