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Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice

Author

Listed:
  • Quynh-Anh Nguyen

    (Stanford University)

  • Peter M. Klein

    (Stanford University)

  • Cheng Xie

    (CODA Biotherapeutics)

  • Katelyn N. Benthall

    (CODA Biotherapeutics)

  • Jillian Iafrati

    (CODA Biotherapeutics)

  • Jesslyn Homidan

    (Stanford University)

  • Jacob T. Bendor

    (CODA Biotherapeutics)

  • Barna Dudok

    (Stanford University
    Baylor College of Medicine)

  • Jordan S. Farrell

    (Stanford University)

  • Tilo Gschwind

    (Stanford University)

  • Charlotte L. Porter

    (Stanford University)

  • Annahita Keravala

    (CODA Biotherapeutics)

  • G. Steven Dodson

    (CODA Biotherapeutics)

  • Ivan Soltesz

    (Stanford University)

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.

Suggested Citation

  • Quynh-Anh Nguyen & Peter M. Klein & Cheng Xie & Katelyn N. Benthall & Jillian Iafrati & Jesslyn Homidan & Jacob T. Bendor & Barna Dudok & Jordan S. Farrell & Tilo Gschwind & Charlotte L. Porter & Anna, 2024. "Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44853-8
    DOI: 10.1038/s41467-024-44853-8
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    References listed on IDEAS

    as
    1. Esther Krook-Magnuson & Caren Armstrong & Mikko Oijala & Ivan Soltesz, 2013. "On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy," Nature Communications, Nature, vol. 4(1), pages 1-8, June.
    2. Dennis Kätzel & Elizabeth Nicholson & Stephanie Schorge & Matthew C. Walker & Dimitri M. Kullmann, 2014. "Chemical–genetic attenuation of focal neocortical seizures," Nature Communications, Nature, vol. 5(1), pages 1-9, September.
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