Molecular mechanism establishing the OFF pathway in vision

Florentina Soto (), Chin-I Lin, Andrew Jo, Ssu-Yu Chou, Ellen G. Harding, Philip A. Ruzycki, Gail K. Seabold, Ronald S. Petralia and Daniel Kerschensteiner ()
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Florentina Soto: Washington University School of Medicine
Chin-I Lin: Washington University School of Medicine
Andrew Jo: Washington University School of Medicine
Ssu-Yu Chou: Washington University School of Medicine
Ellen G. Harding: Washington University School of Medicine
Philip A. Ruzycki: Washington University School of Medicine
Gail K. Seabold: National Institutes of Health
Ronald S. Petralia: National Institutes of Health
Daniel Kerschensteiner: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Parallel ON and OFF (positive- and negative-contrast) pathways fundamental to vision arise at the complex synapse of cone photoreceptors. Cone pedicles form spatially segregated functionally opposite connections with ON and OFF bipolar cells. Here, we discover that mammalian cones express LRFN2, a cell-adhesion molecule, which localizes to the pedicle base. LRFN2 stabilizes basal contacts between cone pedicles and OFF bipolar cell dendrites to guide pathway-specific partner choices, encompassing multiple cell types. In addition, LRFN2 trans-synaptically organizes glutamate receptor clusters, determining the contrast preferences of the OFF pathway. ON and OFF pathways converge in the inner retina to regulate bipolar cell outputs. We analyze LRFN2’s contributions to ON-OFF interactions, pathway asymmetries, and neural and behavioral responses to approaching predators. Our results reveal that LRFN2 controls the formation of the OFF pathway in vision, supports parallel processing in a single synapse, and shapes contrast coding and the detection of visual threats.

Date: 2025
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DOI: 10.1038/s41467-025-59046-0

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