Cone Synaptic function is modulated by the leucine rich repeat (LRR) adhesion molecule LRFN2

Daylight vision is mediated by cone photoreceptors in vertebrates, which synapse with bipolar cells (BCs) and horizontal (HCs) cells. This cone synapse is functionally and anatomically complex, connecting to 8 types of depolarizing (DBC) BCs and 5 types of hyperbolizing BCs (HBCs). The dendrites of DBCs and HCs cells make invaginating ribbon synapses with the cone axon terminal, while HBCs form flat synapses with the cone pedicles. The molecular architecture that underpins this organization is relatively poorly understood. To identify new proteins involved in synapse formation and function we used an unbiased proteomic approach and identified LRFN2 (Leucine-rich repeat and fibronectin III domain-containing 2) as a component of the DBC signaling complex. LRFN2 interacts with TRPM1 and is selectively expressed at cone terminals and co-localizes with PNA, and other DBC signalplex members. In the absence of LRFN2 the cone-mediated photopic electroretinogram b-wave amplitude is reduced. In LRFN2 deficient mice, the synaptic markers: LRIT3, ELFN2, mGluR6, TRPM1 and GPR179 are properly localized. Similarly, LRFN2 expression and localization is not dependent on these synaptic proteins. These data demonstrate that LRFN2 likely interacts with TRPM1 and its absence compromises normal synaptic transmission between cones and cone DBCs cells. Significance StatementSignaling between cone photoreceptors and the downstream bipolar cells is critical to normal vision. Cones synapse with 13 different types of bipolar cells forming an invaginating ribbon synapses with 8 types, and flat synapse with 5 types, to form one of the most complex synapses in the brain. In this report a new protein, LRFN2 (Leucine-rich repeat and fibronectin III domain-containing 2), was identified that is expressed on the cones synapses. Using Lrfn2 knockout mice we show LRFN2 is required for the normal cone signaling.