Optical Stimulation of the Auditory Nerve with Photoswitchable Molecular Prosthetics

Photocontrolled molecular 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. Recently, we have developed a fast photoswitchable tethered ligand of ionotropic glutamate receptors to enable activation of the auditory neurons with light. This compound, named TCPfast, induced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with blue light. 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 firing up to a rate of approximately 1 kHz, matching the fastest optogenetic SGN stimulation. Hence, TCPfast shows that photopharmacology might serve as an alternative tool for the development of optical cochlear implants for hearing restoration [1]. The main results of all these studies will be presented. References: [1] Aida Garrido-Charles, Antoine Huet, Carlo Matera, Anupriya Thirumalai, Jordi Hernando, Amadeu Llebaria, Tobias Moser, Pau Gorostiza. Journal of the American Chemical Society, 2022, 144(21), 9229-9239. doi: 10.1021/jacs.1c12314.