Chemogenetic activation of target neurons expressing insect Ionotropic Receptors in the central nervous system by systemic administration of ligand precursors

Ionotropic Receptors (IRs) in the insect chemosensory system form a variant subfamily belonging to ionotropic glutamate receptors. The IRs-mediated neuronal activation (IRNA) technology allows stimulation of the neurons expressing the receptor in response to specific ligands. In the present study, we developed a strategy for activation of target neurons in the brain through systemic administration with precursors of a specific ligand phenylacetic acid (PhAc) against the complex consisting of IR84a and IR8a subunits. Peripheral administration with methyl ester of PhAc (PhAcM) activated IR84a/IR8a-expressing neurons in the brain of mice and increases the release of neurotransmitters in their nerve terminal regions. (S)-phenylpropionic acid ((S)-PhPr) was newly identified as an IR84a/IR8a ligand, and the peripheral administration with methyl ester of PhPr with the S-configuration [(S)-PhPrM] also caused similar effects on the target neurons. These precursors seemed to be transferred into the brain across the blood-brain barrier, and converted to mature ligands by esterase activity. In addition, cell-type specific expression of IR84a/IR8a complex in the striatum of rats was unilaterally induced with a viral vector based on the Cre-loxP system. Peripheral administration with PhAcM or (S)-PhPrM stimulated the neurotransmitter release in the ipsilateral terminal regions of the vector-injected striatum, and the PhAcM administration resulted in rotational behavior. Besides, the metabolites of the peripherally administered-radiolabeled (S)-PhPrM were accumulated in the IR84a/IR8a-expressing region in the striatum of the vector-injected rats. These results demonstrate that the systemic IRNA technique provides a useful strategy for remote manipulation of the target neurons in the central nervous system.