Photoswitchable molecular prosthetics to photocontrol auditory neurons

Light-controllable chemical tools provide powerful means to manipulate and interrogate biological functions with high spatiotemporal precision and low invasiveness. Our research efforts in the field have focused on the design of reversible photoswitchable compounds to photocontrol enzymes, GPCRs, and ion channels. We have developed phototrexate, the first photoswitchable inhibitor of the human dihydrofolate reductase with demonstrated cytotoxicity in vitro and in zebrafish larvae [1], PAI, a light-controlled dualsteric agonist of muscarinic M2 receptors that enabled the photomodulation of cardiac function in tadpoles and of brain states in mice [2,3], and azodopa, a photoswitchable dopamine D1 receptor agonist that was used to photocontrol swimming behavior in zebrafish larvae and neural activity in mouse cortex [4]. More recently, we have designed a fast photoswitchable tethered ligand of ionotropic glutamate receptors to enable control of the auditory neurons. This compound, named TCPfast, induced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with visible light pulses of few milliseconds. We applied it to the ultrafast synapses of cochlear auditory neurons that encode sound and provide auditory input to the brain. TCPfast functions as a molecular prosthesis that bypasses the neurotransmitter-encoded signal with a photonic signal. Photosensitization of cochlear spiral ganglion neurons (SGNs) by locally administered TCPfast enabled temporally precise light-evoked SGN firing up to a rate of approximately 1 kHz, matching the fastest optogenetic SGN stimulation. Hence, TCPfast-mediated photopharmacology might serve as an interesting alternative to the optogenetic approach for the development of an optical cochlear implant for hearing restoration [5]. The results of these studies will be presented and discussed. [1] Matera C et al. Journal of the American Chemical Society 2018, 140 (46), 15764–15773. [2] Riefolo, F, Matera C et al. Journal of the American Chemical Society 2019, 141 (18), 7628–7636. [3] Barbero‐Castillo A, Riefolo F et al. Advanced Science 2021, 8 (14), 2005027. [4] Matera C et al., manuscript in preparation. [5] Garrido-Charles A, Huet A, Matera C et al., Journal of the American Chemical Society 2022, in press.