Joachimsthaler Anneka, Hauf Katharina, Armbruster Anja, Zayit-Soudry Shiri, Naaman Efrat, Perlman Ido, Leibu Rina, Kurolap Alina, Baris Feldman Hagit, Kremers Jan, Eulenburg Volker
Department of Ophthalmology, University Hospital Erlangen, Erlangen, Germany.
Animal Physiology, Department of Biology, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
Front Mol Neurosci. 2025 May 9;18:1564870. doi: 10.3389/fnmol.2025.1564870. eCollection 2025.
Glycine, along with GABA, constitutes the major inhibitory neurotransmitter in the central nervous system. In the retina, glycinergic neurotransmission is primarily used by amacrine cells that are involved in the lateral processing of visual stimuli in the inner retina. We have previously shown that the high-affinity glycine transporter 1 (GlyT1), that is commonly used as a reliable marker for glycinergic amacrine cells in the retina, is essential for glycinergic neurotransmission by these cells. Abolishment of retinal GlyT1 expression results in a breakdown of glycinergic neurotransmission by AII amacrine cells, but most likely also by other glycinergic amacrine cell populations. However, the impact of loss of glycinergic neurotransmission on retinal signal processing and visually guided behavior, has not yet been elucidated. In this study, the effects of loss of retinal GlyT1 expression in glycinergic amacrine cells on the optomotor reflex and on the photopic and scotopic electroretinogram (ERG) responses were analyzed. We show that retinal GlyT1-deficient mice have normal optomotor responses to rotating black and white stripes. When stimuli with sawtooth luminance profiles were used, thereby differentially activating ON and OFF pathways, the GlyT1 deficient mice showed facilitated responses to ON preferring stimuli, whereas responses to OFF preferring stimuli were unchanged. These findings were corroborated by ERG recordings that showed undistinguishable responses after flash stimulation but revealed differences in the differential processing of ON and OFF preferring stimuli. To determine if the function of retinal GlyT1 is conserved in humans, we analyzed ERG recordings from a patient diagnosed with GlyT1 encephalopathy. We show that GlyT1 deficiency results in marked ERG changes, characterized by an almost complete loss of the "photopic hill" phenomenon, a hill-like appearance of the relationship between the b-wave amplitude and log light stimulus strength under background illumination conditions, and reductions in the ERG oscillatory potentials in the dark- and light-adapted states. Both findings are consistent with an altered interaction between ON- and OFF pathways in the retina. Taken together our data show that glycinergic neurotransmission in the retina has important functions in retinal ON and OFF processing both in mice and humans.
甘氨酸与γ-氨基丁酸（GABA）共同构成中枢神经系统中的主要抑制性神经递质。在视网膜中，甘氨酸能神经传递主要由无长突细胞利用，这些细胞参与视网膜内层视觉刺激的侧向处理。我们之前已经表明，高亲和力甘氨酸转运体1（GlyT1）通常用作视网膜中甘氨酸能无长突细胞的可靠标志物，对于这些细胞的甘氨酸能神经传递至关重要。视网膜GlyT1表达的缺失会导致AII无长突细胞的甘氨酸能神经传递中断，但很可能其他甘氨酸能无长突细胞群体也会如此。然而，甘氨酸能神经传递丧失对视网膜信号处理和视觉引导行为的影响尚未阐明。在本研究中，分析了甘氨酸能无长突细胞中视网膜GlyT1表达缺失对视动反射以及明视和暗视视网膜电图（ERG）反应的影响。我们发现，视网膜GlyT1缺陷小鼠对旋转的黑白条纹具有正常的视动反应。当使用具有锯齿状亮度分布的刺激，从而差异性激活ON和OFF通路时，GlyT1缺陷小鼠对偏好ON的刺激表现出促进反应，而对偏好OFF的刺激的反应则未改变。ERG记录证实了这些发现，其显示闪光刺激后反应无差异，但揭示了对偏好ON和OFF的刺激的差异处理存在差异。为了确定视网膜GlyT1的功能在人类中是否保守，我们分析了一名被诊断患有GlyT1脑病患者的ERG记录。我们发现，GlyT1缺陷导致明显的ERG变化，其特征是“明视峰”现象几乎完全丧失，即在背景照明条件下b波振幅与对数光刺激强度之间呈现出峰状关系，以及在暗适应和明适应状态下ERG振荡电位降低。这两个发现都与视网膜中ON和OFF通路之间相互作用的改变一致。综上所述，我们的数据表明，视网膜中的甘氨酸能神经传递在小鼠和人类的视网膜ON和OFF处理中都具有重要功能。
