Commun Biol, co-auth.: group Benton

Chemogenetic activation of mammalian brain neurons expressing insect Ionotropic Receptors by systemic ligand precursor administration

Yoshio Iguchi 1Ryoji Fukabori 1Shigeki Kato 1Kazumi Takahashi 2Satoshi Eifuku 2Yuko Maejima 3Kenju Shimomura 3Hiroshi Mizuma 4 5Aya Mawatari 6Hisashi Doi 6 7Yilong Cui 8Hirotaka Onoe 9Keigo Hikishima 10Makoto Osanai 11Takuma Nishijo 12 13Toshihiko Momiyama 12Richard Benton 14Kazuto Kobayashi 15

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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.