LRIT3 expression in cone photoreceptors restores post-synaptic bipolar cell signalplex assembly and function in Lrit3^-/- mice

Abstract

Complete congenital stationary night blindness (cCSNB) is a heterogeneous disorder characterized by poor dim light vision, myopia, and nystagmus, that is caused by mutations in genes critical for signal transmission between photoreceptors and depolarizing bipolar cells (DBCs). One such gene, LRIT3, is required for assembly of the post-synaptic signaling complex (signalplex) at the dendritic tips of DBCs, although the number of signalplex components impacted is greater in cone DBCs than in rod bipolar cells. This difference raises the possibility that LRIT3 is expressed both pre- and post-synaptically at cone terminals. Here we show that rAAV-mediated expression of LRIT3 in cones results in robust rescue of cone DBC signalplex components and restores downstream visual function, as measured by the light adapted ERG b-wave and electrophysiological recordings of BCs and RGCs. These data show that LRIT3 successfully restores function to cone DBCs in a trans-synaptic manner, potentially paving the way for therapeutic intervention in LRIT3-associated cCSNB.