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Molecular mechanism establishing the OFF pathway in vision

Author

Listed:
  • Florentina Soto

    (Washington University School of Medicine)

  • Chin-I Lin

    (Washington University School of Medicine
    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
    National Institutes of Health)

  • Daniel Kerschensteiner

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

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.

Suggested Citation

  • Florentina Soto & Chin-I Lin & Andrew Jo & Ssu-Yu Chou & Ellen G. Harding & Philip A. Ruzycki & Gail K. Seabold & Ronald S. Petralia & Daniel Kerschensteiner, 2025. "Molecular mechanism establishing the OFF pathway in vision," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59046-0
    DOI: 10.1038/s41467-025-59046-0
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    References listed on IDEAS

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    1. Anthony D. Lien & Massimo Scanziani, 2018. "Cortical direction selectivity emerges at convergence of thalamic synapses," Nature, Nature, vol. 558(7708), pages 80-86, June.
    2. Joshua Hahn & Aboozar Monavarfeshani & Mu Qiao & Allison H. Kao & Yvonne Kölsch & Ayush Kumar & Vincent P. Kunze & Ashley M. Rasys & Rose Richardson & Joseph B. Wekselblatt & Herwig Baier & Robert J. , 2023. "Evolution of neuronal cell classes and types in the vertebrate retina," Nature, Nature, vol. 624(7991), pages 415-424, December.
    3. Naoko Morimura & Hiroki Yasuda & Kazuhiko Yamaguchi & Kei-ichi Katayama & Minoru Hatayama & Naoko H. Tomioka & Maya Odagawa & Akiko Kamiya & Yoshimi Iwayama & Motoko Maekawa & Kazuhiko Nakamura & Hide, 2017. "Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice," Nature Communications, Nature, vol. 8(1), pages 1-17, August.
    4. Chad P. Grabner & Daiki Futagi & Jun Shi & Vytas Bindokas & Katsunori Kitano & Eric A. Schwartz & Steven H. DeVries, 2023. "Mechanisms of simultaneous linear and nonlinear computations at the mammalian cone photoreceptor synapse," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    5. Maximilian Joesch & Bettina Schnell & Shamprasad Varija Raghu & Dierk F. Reiff & Alexander Borst, 2010. "ON and OFF pathways in Drosophila motion vision," Nature, Nature, vol. 468(7321), pages 300-304, November.
    6. Katrin Franke & Philipp Berens & Timm Schubert & Matthias Bethge & Thomas Euler & Tom Baden, 2017. "Inhibition decorrelates visual feature representations in the inner retina," Nature, Nature, vol. 542(7642), pages 439-444, February.
    7. Sarah Strauss & Maria M. Korympidou & Yanli Ran & Katrin Franke & Timm Schubert & Tom Baden & Philipp Berens & Thomas Euler & Anna L. Vlasits, 2022. "Center-surround interactions underlie bipolar cell motion sensitivity in the mouse retina," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    8. Moritz Helmstaedter & Kevin L. Briggman & Srinivas C. Turaga & Viren Jain & H. Sebastian Seung & Winfried Denk, 2013. "Connectomic reconstruction of the inner plexiform layer in the mouse retina," Nature, Nature, vol. 500(7461), pages 168-174, August.
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