Chemical–genetic attenuation of focal neocortical seizures

Dennis Kätzel, Elizabeth Nicholson, Stephanie Schorge, Matthew C. Walker and Dimitri M. Kullmann ()
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Dennis Kätzel: UCL Institute of Neurology, Queen Square
Elizabeth Nicholson: UCL Institute of Neurology, Queen Square
Stephanie Schorge: UCL Institute of Neurology, Queen Square
Matthew C. Walker: UCL Institute of Neurology, Queen Square
Dimitri M. Kullmann: UCL Institute of Neurology, Queen Square

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4847

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