Divergent mechanisms of neural adaptation and instability in the mammalian retina

Jacob Khoussine¹, Abhilash Sawant², Sapan Gupta³, Haoshen Zhai³, Pawan K Shahi⁴, Bikash R Pattnaik⁵, Raunak Sinha⁶, Mrinalini Hoon⁷

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Medical Scientist and Cellular and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁶ McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: mhoon@wisc.edu.

PMID: 40580962
PMCID: PMC12225612 (available on 2026-06-27)
DOI: 10.1016/j.cub.2025.06.015

Divergent mechanisms of neural adaptation and instability in the mammalian retina

Jacob Khoussine et al. Curr Biol. 2025.

. 2025 Jul 21;35(14):3381-3395.e4.

doi: 10.1016/j.cub.2025.06.015. Epub 2025 Jun 27.

Authors

Jacob Khoussine¹, Abhilash Sawant², Sapan Gupta³, Haoshen Zhai³, Pawan K Shahi⁴, Bikash R Pattnaik⁵, Raunak Sinha⁶, Mrinalini Hoon⁷

Affiliations

¹ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Medical Scientist and Cellular and Molecular Biology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA.
² Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
³ Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁴ McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁵ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Pediatrics, University of Wisconsin-Madison, Madison, WI 53706, USA.
⁶ McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA.
⁷ Department of Ophthalmology and Visual Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA; McPherson Eye Research Institute, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, University of Wisconsin-Madison, Madison, WI 53705, USA. Electronic address: mhoon@wisc.edu.

PMID: 40580962
PMCID: PMC12225612 (available on 2026-06-27)
DOI: 10.1016/j.cub.2025.06.015

Abstract

Sensory circuits can exhibit remarkable resilience to disruption, often maintaining function through recruitment of compensatory mechanisms. In the mammalian retina, the balance between ON and OFF pathways that encode distinct luminance profiles is essential for processing visual information. How selective disruption of one input stream can trigger adaptive and/or compensatory measures in retinal output neurons is not fully understood. To determine how retinal output circuits can adapt to different degrees of input suppression, we genetically suppressed the ON pathway input in two models with partial (50%) and complete (100%) ON pathway blockade. We used single-cell electrophysiology to record intrinsic properties, synaptic inputs, and spike outputs of alpha retinal ganglion cell (RGC) types that serve as primary output channels. Complementary immunohistochemistry assessed structural changes in excitatory and inhibitory synaptic protein expression within individual RGCs. We found that 50% ON pathway suppression triggers adaptive scaling of excitatory synaptic proteins in ON and OFF RGCs that are aimed at preserving visual function. In contrast, complete suppression leads to maladaptive intrinsic alterations and cyclical instability in specific OFF-RGC types, impairing visual processing. We also observed luminance-level-dependent alterations in the OFF pathway output and contrast-encoding abilities after ON pathway suppression. Our findings reveal that the extent of input suppression determines whether compensatory mechanisms are beneficial or detrimental, offering new insights into retinal plasticity mechanisms. Uncovering these mechanisms expands our knowledge of sensory neuroplasticity, revealing potential therapeutic strategies for ameliorating dysfunction in disease conditions of ON pathway suppression, such as congenital stationary night blindness.

Keywords: ON pathway suppression; compensatory mechanisms; homeostatic plasticity; retinal ganglion cell; synaptic imbalance.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Divergent mechanisms of neural adaptation and instability in the mammalian retina

Affiliations

Divergent mechanisms of neural adaptation and instability in the mammalian retina

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous