Narayan Daniel S, Ao Jack, Wood John P M, Casson Robert J, Chidlow Glyn
Ophthalmic Research Laboratories, Discipline of Ophthalmology and Visual Sciences, University of Adelaide, Level 7 Adelaide Health and Medical Sciences Building, North Terrace, Adelaide, SA, 5000, Australia.
BMC Neurosci. 2019 Sep 3;20(1):46. doi: 10.1186/s12868-019-0528-2.
The 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.
Outer 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.
The results of the present study provide valuable insights into cone degeneration in the Rd1 mouse, substantiating and extending conclusions drawn from earlier studies.
Pde6brd1（Rd1）小鼠被广泛用作人类视网膜色素变性的小鼠模型。了解视锥细胞变性的时空模式对于评估潜在治疗方法很重要。在本研究中，我们对Rd1小鼠中S-和M/L-视蛋白视锥细胞外段和细胞体变性的时空模式进行了系统表征，描述了Rd1视网膜中双视锥细胞的分布和比例，并研究了视锥细胞变性期间小胶质细胞激活的动力学。
S-和M/L-视锥细胞的外段比它们的细胞体退化得快得多。在中央视网膜中，到P21时，S-和M/L-视蛋白外段的损失基本完成，在周边视网膜中，到P45时90%完成。相比之下，S-和M/L-视蛋白细胞体的退化速度较慢。S-视蛋白和M/L-视蛋白细胞体的退化速度存在明显的半球不对称性。M/L-视蛋白视锥细胞在视网膜上部对退化更具弹性，而S-视蛋白视锥细胞在视网膜下部相对保留。此外，视锥细胞外段和细胞体的退化在中央视网膜比周边视网膜发生得更快。在P14时，视网膜上部真正的S-视锥细胞占少数，真正的M/L-视蛋白视锥细胞和双视锥细胞的数量更多，而其他三个视网膜象限中真正的S-视锥细胞、真正的M/L-视锥细胞和双视锥细胞数量大致相似。在P60时，视网膜上部、鼻侧和颞侧象限中约50%存活的视锥细胞是双视锥细胞。相比之下，P60时视网膜下部周边几乎只含有真正的S-视锥细胞，双视锥细胞占极少数。在视杆细胞崩解期间，小胶质细胞数量和活性受到刺激，在中央视网膜视锥细胞外段退化和视锥细胞体丢失期间保持相对较高水平，此后在周边视网膜视锥细胞体缓慢退化期间下降。
本研究结果为Rd1小鼠视锥细胞变性提供了有价值的见解，证实并扩展了早期研究得出的结论。
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