Optogenetic Modulation of TrkB Signaling in the Mouse Brain

Abstract

Optogenetic activation of receptors has advantages compared with chemical or ligand treatment because of its high spatial and temporal precision. Especially in the brain, the use of a genetically encoded light-tunable receptor is superior to direct infusion or systemic drug treatment. We applied light-activatable TrkB receptors in the mouse brain with reduced basal activity by incorporating Cry2PHR mutant, Opto-cytTrkB(E281A). Upon AAV mediated gene delivery, this form was expressed at sufficient levels in the mouse hippocampus (HPC) and medial entorhinal cortex (MEC) retaining normal canonical signal transduction by the blue light stimulus, even by delivery of noninvasive LED light on the mouse head. Within target cells, where its expression was driven by a cell type-specific promoter, Opto-cytTrkB(E281A)-mediated TrkB signaling could be controlled by adjusting light-stimulating conditions. We further demonstrated that Opto-cytTrkB(E281A) could locally induce TrkB signaling in axon terminals in the MEC-HPC. In summary, Opto-cytTrkB(E281A) will be useful for elucidating time- and region-specific roles of TrkB signaling ranging from cellular function to neural circuit mechanisms. • Optogenetic spatiotemporal signaling activation has benefits compared with chemicals. • Optogenetic TrkB induces signaling in the mouse brain, even noninvasive light. • Compared with ligand, optogenetic TrkB induces type-specific signaling modulation. • Local Opto-cytTrkB activation can be induced in axon terminals in the MEC-HPC. • Optogenetic TrkB is suitable for the circuit, as well as intracellular applications.