Khoussine Jacob, Sawant Abhilash, Gupta Sapan, Zhai Haoshen, Shahi Pawan K, Pattnaik Bikash R, Sinha Raunak, Hoon Mrinalini
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.
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.
Curr Biol. 2025 Jun 24. doi: 10.1016/j.cub.2025.06.015.
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.
感觉回路对破坏可表现出显著的恢复力，常常通过启用补偿机制来维持功能。在哺乳动物视网膜中，编码不同亮度特征的ON和OFF通路之间的平衡对于视觉信息处理至关重要。一种输入流的选择性破坏如何在视网膜输出神经元中触发适应性和/或补偿性措施尚不完全清楚。为了确定视网膜输出回路如何适应不同程度的输入抑制，我们在两种模型中通过基因手段抑制ON通路输入，一种是部分（50%）阻断ON通路，另一种是完全（100%）阻断ON通路。我们使用单细胞电生理学记录作为主要输出通道的α视网膜神经节细胞（RGC）类型的内在特性、突触输入和动作电位输出。互补免疫组织化学评估了单个RGC内兴奋性和抑制性突触蛋白表达的结构变化。我们发现，50%的ON通路抑制会触发ON和OFF RGC中兴奋性突触蛋白的适应性缩放，目的是保持视觉功能。相比之下，完全抑制会导致特定OFF-RGC类型出现适应不良的内在改变和周期性不稳定，损害视觉处理。我们还观察到ON通路抑制后OFF通路输出和对比度编码能力的亮度水平依赖性改变。我们的研究结果表明，输入抑制的程度决定了补偿机制是有益还是有害，为视网膜可塑性机制提供了新的见解。揭示这些机制扩展了我们对感觉神经可塑性的认识，为改善ON通路抑制疾病状态（如先天性静止性夜盲）中的功能障碍揭示了潜在的治疗策略。
