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- Title
Chemogenetic activation of mammalian brain neurons expressing insect Ionotropic Receptors by systemic ligand precursor administration.
- Authors
Iguchi, Yoshio; Fukabori, Ryoji; Kato, Shigeki; Takahashi, Kazumi; Eifuku, Satoshi; Maejima, Yuko; Shimomura, Kenju; Mizuma, Hiroshi; Mawatari, Aya; Doi, Hisashi; Cui, Yilong; Onoe, Hirotaka; Hikishima, Keigo; Osanai, Makoto; Nishijo, Takuma; Momiyama, Toshihiko; Benton, Richard; Kobayashi, Kazuto
- Abstract
Chemogenetic approaches employing ligand-gated ion channels are advantageous regarding manipulation of target neuronal population functions independently of endogenous second messenger pathways. Among them, Ionotropic Receptor (IR)-mediated neuronal activation (IRNA) allows stimulation of mammalian neurons that heterologously express members of the insect chemosensory IR repertoire in response to their cognate ligands. In the original protocol, phenylacetic acid, a ligand of the IR84a/IR8a complex, was locally injected into a brain region due to its low permeability of the blood-brain barrier. To circumvent this invasive injection, we sought to develop a strategy of peripheral administration with a precursor of phenylacetic acid, phenylacetic acid methyl ester, which is efficiently transferred into the brain and converted to the mature ligand by endogenous esterase activities. This strategy was validated by electrophysiological, biochemical, brain-imaging, and behavioral analyses, demonstrating high utility of systemic IRNA technology in the remote activation of target neurons in the brain. This study established a strategy for systemic administration of prodrugs to induce activation in target neurons in the mammalian brain that express Ionotropic Receptors derived from the insect Drosophila melanogaster.
- Subjects
BLOOD-brain barrier; LIGAND-gated ion channels; PHENYLACETIC acid; NEURONS; DROSOPHILA melanogaster; METHYL formate
- Publication
Communications Biology, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-024-06223-4