Glaucoma is an age-related neurodegenerative disease that is commonly associated with sensitivity to intraocular pressure. The disease selectively targets retinal ganglion cells (RGCs) and constituent axons. RGC axons are rich in voltage-gated sodium channels, which are essential for action potential initiation and regeneration. Here, we identified voltage-dependent sodium channel, NaV1.2, in the retina, examined how this channel contributes to RGC light responses, and monitored NaV1.2 mRNA and protein expression in the retina during progression of modeled glaucoma. We found NaV1.2 is predominately localized in ganglion cell intraretinal axons with dispersed expression in the outer and inner plexiform layers. We showed Phrixotoxin-3, a potent NaV1.2 channel blocker, significantly decreased RGC electrical activity in a dose-dependent manner with an IC50 of 40 nM. Finally, we found four weeks of raised intraocular pressure (30% above baseline) significantly increased NaV1.2 mRNA expression but reduced NaV1.2 protein level in the retina up to 57% (p < 0.001). Following prolonged intraocular pressure elevation, NaV1.2 protein expression particularly diminished at distal sections of ganglion cell intraretinal axons (p ≤ 0.01). Our results suggest NaV1.2 might be a therapeutic target during disease progression to maintain RGC excitability, preserving presynaptic connections through action potential backpropagation.

中文翻译：

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眼压升高会降低视网膜神经节细胞轴突中电压门控钠通道 NaV1.2 蛋白的表达。


青光眼是一种与年龄相关的神经退行性疾病，通常与眼压敏感性有关。该疾病选择性地针对视网膜神经节细胞（RGC）和组成轴突。 RGC 轴突富含电压门控钠通道，这对于动作电位启动和再生至关重要。在这里，我们确定了视网膜中的电压依赖性钠通道 NaV1.2，检查了该通道如何促进 RGC 光反应，并监测了模型青光眼进展过程中视网膜中 NaV1.2 mRNA 和蛋白质的表达。我们发现 NaV1.2 主要定位于神经节细胞视网膜内轴突，并在外丛状层和内丛状层中分散表达。我们发现 Phrixotoxin-3 是一种有效的 NaV1.2 通道阻断剂，能够以剂量依赖性方式显着降低 RGC 电活动，IC50 为 40 nM。最后，我们发现眼压升高（高于基线 30%）四个星期显着增加了 NaV1.2 mRNA 表达，但视网膜中 NaV1.2 蛋白水平降低了 57%（p < 0.001）。眼压长时间升高后，神经节细胞视网膜内轴突远端部分的 NaV1.2 蛋白表达尤其减少 (p ≤ 0.01)。我们的结果表明 NaV1.2 可能是疾病进展期间维持 RGC 兴奋性的治疗靶点，通过动作电位反向传播保持突触前连接。