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 modulate postsynaptic neurons 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 comparable efficacy under the conditions tested. By design, the modularity of the platform permits the use of luciferases and opsins ranging in brightness and light sensitivity, with the luciferase targeted to different subcellular regions of the presynaptic neuron, and the postsynaptic opsin being excitatory or inhibitory. Our results demonstrate the utility and versatility of Interluminescence to mediate synapse-specific transmission that is either activity-dependent or activity-independent.