Control of Synaptic Communication through Molecularly Engineered Bioluminescence Light Emission and Sensing.

Synapses are sites of intercellular communication between neurons and from neurons to target organs, and of signal integration that underly physiological and behavioral responses. We have developed a modular platform, Interluminescence (Int), for experimental control of synaptic transmission: bioluminescent light, generated by a luciferase oxidizing a luciferin, from a presynaptic neuron is used to activate transsynaptic optogenetic ion channels in the postsynaptic neuron. Two strategies can activate or silence postsynaptic neurons in vivo in the presence of luciferin. In the 'Act-Int' approach, a luciferase is genetically expressed in synaptic vesicles and released during depolarization-induced presynaptic vesicle fusion and exocytosis. In the 'Persist-Int' approach, a luciferase is tethered to the presynaptic membrane where it can support sustained transsynaptic signaling. Both strategies can activate postsynaptic neurons with similar efficacy. By design, the modularity of the platform permits the use of luciferases and opsins ranging in brightness and light sensitivity, and the luciferase can be targeted to different subcellular regions of the presynaptic neuron. Our results demonstrate the utility and versatility of Interluminescence to mediate synapse-specific transmission that is either activity-dependent or activity-independent.