Publication Date
1-18-2024
Journal
Nature Communications
DOI
10.1038/s41467-024-44853-8
PMID
38238329
PMCID
PMC10796428
PubMedCentral® Posted Date
1-18-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Mice, Male, Humans, Animals, Receptors, Cholinergic, alpha7 Nicotinic Acetylcholine Receptor, Receptors, Nicotinic, Nicotinic Agonists, Acetylcholine, Seizures, Epilepsy
Abstract
Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed BARNI (Bradanicline- and Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy.