TY  - JOUR
UR  - http://dx.doi.org/10.1038/ncomms4847
ID  - discovery1431152
N2  - 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.
AV  - public
Y1  - 2014/05/27/
TI  - Chemical-genetic attenuation of focal neocortical seizures.
JF  - Nat Commun
A1  - Kätzel, D
A1  - Nicholson, E
A1  - Schorge, S
A1  - Walker, MC
A1  - Kullmann, DM
VL  - 5
N1  - © 2014 Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 3.0
Unported License. The images or other third party material in this
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in the credit line; if the material is not included under the Creative Commons license,
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To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
ER  -