Presynaptic LRIT3 Expression Trans-Synaptically Organizes Postsynaptic Trafficking of TRPM1 in Rod Bipolar Cells and Restores Vision in Dim Light

Abstract

Synaptic function requires the precise alignment of pre and post-synaptic signaling complexes. At the first synapse in the retina, each rod photoreceptor connects via an invaginating ribbon synapse to two postsynaptic partners, rod bipolar cells (RBCs) and horizontal (HCs) cells. The RBCs signal rod-mediated changes in synaptic glutamate using a signalplex initiated by the metabotropic glutamate receptor 6, mGluR6, and culminating with modulation of the transient receptor potential cation channel, melastatin subfamily 1 (TRPM1) channel. One member of this signalplex, LRIT3, when deleted eliminates signaling and causes complete congenital stationary night blindness (cCSNB). The mechanism by which LRIT3 impacts the signalplex and its subcellular location are unknown. Using in situ hybridization, and restoring expression to Lrit3-/- mice by the use of recombinant adenoassociated virus (rAAV) vector-mediated transduction, we show LRIT3 is expressed in rod photoreceptors. This presynaptic restoration restores postsynaptic TRPM1 expression to the RBC dendrites, and scotopic, but not photopic, retinal visual function. Thus, LRIT3 acts as a trans-synaptic organizer of the RBC signalplex.