BackgroundThe Pde6brd1 (Rd1) mouse is widely used as a murine model for human retinitis pigmentosa. Understanding the spatio-temporal patterns of cone degeneration is important for evaluating potential treatments. In the present study we performed a systematic characterization of the spatio-temporal patterns of S- and M/L-opsin+ cone outer segment and cell body degeneration in Rd1 mice, described the distribution and proportion of dual cones in Rd1 retinas, and examined the kinetics of microglial activation during the period of cone degeneration.ResultsOuter segments of S- and M/L-cones degenerated far more rapidly than their somas. Loss of both S- and M/L-opsin+ outer segments was fundamentally complete by P21 in the central retina, and 90% complete by P45 in the peripheral retina. In comparison, degeneration of S- and M/L-opsin+ cell bodies proceeded at a slower rate. There was a marked hemispheric asymmetry in the rate of S-opsin+ and M/L-opsin+ cell body degeneration. M/L-opsin+ cones were more resilient to degeneration in the superior retina, whilst S-opsin+ cones were relatively preserved in the inferior retina. In addition, cone outer segment and cell body degeneration occurred far more rapidly in the central than the peripheral retina. At P14, the superior retina comprised a minority of genuine S-cones with a much greater complement of genuine M/L-opsin cones and dual cones, whilst the other three retinal quadrants had broadly similar numbers of genuine S-cones, genuine M/L-cones and dual cones. At P60, approximately 50% of surviving cones in the superior, nasal and temporal quadrants were dual cones. In contrast, the inferior peripheral retina at P60 contained almost exclusively genuine S-cones with a tiny minority of dual cones. Microglial number and activity were stimulated during rod breakdown, remained relatively high during cone outer segment degeneration and loss of cone somas in the central retina, and decreased thereafter in the period coincident with slow degeneration of cone cell bodies in the peripheral retina.ConclusionThe results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.

中文翻译：

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视网膜色素变性 Rd1 小鼠模型中 S 和 M/L 视锥细胞变性的时空特征

背景 Pde6brd1 (Rd1) 小鼠被广泛用作人类视网膜色素变性的小鼠模型。了解视锥退化的时空模式对于评估潜在的治疗方法很重要。在本研究中，我们对 Rd1 小鼠中 S-和 M/L-视蛋白 + 视蛋白 + 视锥外段和细胞体变性的时空模式进行了系统表征，描述了 Rd1 视网膜中双视锥的分布和比例，并检查了视锥细胞退化期间小胶质细胞活化的动力学。结果 S-和 M/L-视锥细胞的外段退化远比它们的胞体快得多。S-和M/L-视蛋白+外段的缺失在中央视网膜中由P21基本完成，在周边视网膜中由P45完成90%。相比下，S-和M/L-视蛋白+细胞体的退化以较慢的速度进行。S-视蛋白+和M/L-视蛋白+细胞体变性的速率存在明显的半球不对称性。M/L-视蛋白+视锥细胞在上层视网膜中对退化的抵抗力更强，而S-视蛋白+视锥细胞在下层视网膜中相对保留。此外，中央部的视锥外段和细胞体变性发生得比周边视网膜快得多。在 P14 时，上层视网膜包含少数真正的 S 锥体，具有更多的真正 M/L 视蛋白锥体和双锥体，而其他三个视网膜象限具有大致相似数量的真正 S 锥体、真正的 M/ L 锥体和双锥体。在 P60 时，上、鼻和颞象限中大约 50% 的存活锥体是双锥体。相比之下，P60 处的下周边视网膜几乎完全包含真正的 S 锥体和极少数双锥体。小胶质细胞数量和活性在视杆分解过程中受到刺激，在视锥外节变性和中央视网膜视锥体细胞丢失时保持较高水平，此后在与周边视网膜视锥细胞体缓慢退化相一致的时期内减少。本研究为 Rd1 小鼠的视锥细胞变性提供了有价值的见解，证实并扩展了从早期研究中得出的结论。