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Interplay between cell-adhesion molecules governs synaptic wiring of cone photoreceptors

Significance Humans, like most diurnal species, utilize cone photoreceptors to enable daylight vision. They detect color, cover a wide range of light intensities, and sustain fast responsiveness to faithfully sample rapidly changing scenery. All of these features that allow us to accurately see the world depend on the ability of cones to transmit their light-evoked signals to the brain. For this, cones form functional contacts with their downstream neurons—a process known as “synaptic wiring.” The molecular mechanisms that mediate establishment of cone synaptic contacts are largely unknown. Our studies fill this gap by identifying a set of molecules involved in functional wiring of cones. Establishment of functional synaptic connections in a selective manner is essential for nervous system operation. In mammalian retinas, rod and cone photoreceptors form selective synaptic connections with different classes of bipolar cells (BCs) to propagate light signals. While there has been progress in elucidating rod wiring, molecular mechanisms used by cones to establish functional synapses with BCs have remained unknown. Using an unbiased proteomic strategy in cone-dominant species, we identified the cell-adhesion molecule ELFN2 to be pivotal for the functional wiring of cones with the ON type of BC. It is selectively expressed in cones and transsynaptically recruits the key neurotransmitter receptor mGluR6 in ON-BCs to enable synaptic transmission. Remarkably, ELFN2 in cone terminals functions in synergy with a related adhesion molecule, ELFN1, and their concerted interplay during development specifies selective wiring and transmission of cone signals. These findings identify a synaptic connectivity mechanism of cones and illustrate how interplay between adhesion molecules and postsynaptic transmitter receptors orchestrates functional synaptic specification in a neural circuit.