RT Journal Article SR Electronic T1 LRIT3 is Required for Nyctalopin Expression and Normal ON and OFF Pathway Signaling in the Retina JF eneuro JO eNeuro FD Society for Neuroscience SP ENEURO.0002-20.2020 DO 10.1523/ENEURO.0002-20.2020 VO 7 IS 1 A1 Hasan, Nazarul A1 Pangeni, Gobinda A1 Ray, Thomas A. A1 Fransen, Kathryn M. A1 Noel, Jennifer A1 Borghuis, Bart G. A1 McCall, Maureen A. A1 Gregg, Ronald G. YR 2020 UL http://www.eneuro.org/content/7/1/ENEURO.0002-20.2020.abstract AB The first retinal synapse, photoreceptor→bipolar cell (BC), is both anatomically and functionally complex. Within the same synaptic region, a change in presynaptic glutamate release is sensed by both ON BCs (DBCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs (HBCs) via ionotropic glutamate receptors to establish parallel signaling pathways that preferentially encode light increments (ON) or decrements (OFF), respectively. The synaptic structural organization of ON and OFF-type BCs at the photoreceptor terminal differs. DBCs make an invaginating synapse that contains a diverse but incompletely understood complex of interacting proteins (signalplex). HBCs make primarily flat contacts that contain an apparent different set of proteins that is equally uncharacterized. LRIT3 is a synaptic protein known to be essential for ON pathway visual function. In both male and female mice, we demonstrate that LRIT3 interacts with and is required for expression of nyctalopin, and thus TRPM1 at all DBC dendritic tips, but DBC signalplex components are not required for LRIT3 expression. Using whole-cell and multielectrode array (MEA) electrophysiology and glutamate imaging, we demonstrate that the loss of LRIT3 impacts both ON and OFF signaling pathway function. Without LRIT3, excitatory input to type 1 BCs is reduced, as are the visually evoked responses of many OFF retinal ganglion cells (RGCs). We conclude that the absence of LRIT3 expression disrupts excitatory input to OFF BCs and, thus disrupts the normal function of OFF RGCs.