Emery Douglas, Vukmanic Eric, Wang Yekai, Eminhizer Mark, Wang Fuhua, Lu Xiaoqin, Wang Wei, Kini Ashwini, Chen Yao, Fortuny Enzo, James Robert F, Liu Yongqing, Du Jianhai, Dean Douglas C
Department of Medicine, Brown Cancer Center, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
Departments of Ophthalmology and Visual Sciences and Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USA.
Sci Adv. 2025 Jun 27;11(26):eadx2050. doi: 10.1126/sciadv.adx2050.
Photoreceptors signal ON and OFF pathways via a synapse with bipolar cells that are transmitted to retinal ganglion cells (RGCs) for luminance and contrast detection. Retinal neurons metabolize glucose whose transport is mediated by photoreceptor contact with the adjacent retinal pigment epithelium (RPE). Rod loss in retinitis pigmentosa (RP) reduces RPE contact, diminishing glucose transport. We show diminished glucose leads to light hyperresponsiveness driven by deregulated ON cone bipolar signaling. Transmission of this constitutive signal to RGCs causes ON > OFF signaling imbalance and failure to detect luminance and contrast changes. Our results suggest that the aspartate-malate shuttle in GABAergic amacrine cells metabolizes glucose to γ-aminobutyric acid (GABA), which in turn regulates the ON cone bipolar signal. GABA receptor agonists such as Ativan are a widely prescribed first-line therapy for seizures initiated by low brain GABA, and we show that Ativan restores ON cone bipolar cell regulation in RP where retinal GABA is diminished, reestablishing luminance and contrast detection.
光感受器通过与双极细胞形成的突触来传递开和关通路的信号，这些信号会被传输到视网膜神经节细胞（RGCs）以进行亮度和对比度检测。视网膜神经元代谢葡萄糖，其转运由光感受器与相邻的视网膜色素上皮（RPE）接触介导。视网膜色素变性（RP）中的视杆细胞丧失会减少RPE接触，从而减少葡萄糖转运。我们发现葡萄糖减少会导致由失调的开锥双极信号驱动的光超敏反应。这种组成性信号向RGCs的传递会导致开>关信号失衡，以及无法检测亮度和对比度变化。我们的结果表明，GABA能无长突细胞中的天冬氨酸-苹果酸穿梭将葡萄糖代谢为γ-氨基丁酸（GABA），而GABA反过来又调节开锥双极信号。像阿替万这样的GABA受体激动剂是一种广泛使用的一线治疗药物，用于治疗因大脑GABA水平低引发的癫痫，并且我们发现阿替万可恢复视网膜GABA减少的RP中锥双极细胞的调节，从而重新建立亮度和对比度检测。
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