Fast photoswitchable molecular prosthetics control neuronal activity in the cochlea

Artificial control of neuronal activity enables studies of neural circuits and restoration of neural function. Direct, rapid, and sustained photocontrol of intact neurons could overcome shortcomings of established electrical stimulation such as poor selectivity. We have developed fast photoswitchable ligands of glutamate receptors to establish such control in the auditory system. The new photoswitchable ligands produced photocurrents in untransfected neurons upon covalently tethering to endogenous glutamate receptors and activating them reversibly with visible light pulses of few milliseconds. As a proof of concept of these molecular prostheses, we apply them to the ultrafast synapses of auditory neurons of the cochlea that encode sound and provide auditory input to the brain. This drug-based method affords kilohertz rate stimulation of auditory neurons of adult gerbils without genetic manipulation that would be required for their optogenetic control. The new photoswitchable ligands are also broadly applicable to spatiotemporally control fast spiking interneurons in the brain.