Abstract
Following retinal degeneration, retinal remodeling can cause neuronal microcircuits to undergo structural alterations, which particularly affect the dendrites of bipolar cells. However, the mechanisms and functional consequences of such changes remain unclear. Here, we used Royal College of Surgeon (RCS) rats as a model of retinal degeneration, to study structural changes in rod bipolar cells (RBCs) and the underlying mechanisms of these changes. We found that, with retinal degeneration, RBC dendrites extended into the outer nuclear layer (ONL) of the retina, and the ectopic dendrites formed synapses with the remaining photoreceptors. This ectopic neuritogenesis was associated with brain-derived neurotrophic factor (BDNF) – expression of which was negatively regulated by miR-125b-5p. Overexpression of miR-125b-5p in the retinae of RCS rats diminished RBC ectopic dendrites, and compromised the b-wave of the flash electroretinogram (ERG). In contrast, down-regulation of miR-125b-5p (or exogenous BDNF treatment) increased RBC ectopic dendrites, and improved b-wave. Furthermore, we showed that the regulation of ectopic neuritogenesis by BDNF occurred via the downstream modulation of the TrkB-CREB signaling pathway. Based on these findings, we conclude that ectopic dendrites are likely to be providing functional benefits and that, in RCS rats, miR-125b-5p regulates ectopic neuritogenesis by RBCs through modulation of the BDNF-TrkB-CREB pathway. This suggests that therapies that reduce miR-125b-5p expression could be beneficial in human retinal degenerative disease.
Highlights
Retinitis pigmentosa (RP) is a form of inherited retinal degeneration that causes blindness in humans, due to a progressive loss of photoreceptors
In the retinae of Royal College of Surgeon (RCS) rats, the thickness of the outer nuclear layer (ONL) gradually decreased from P17 to P90, which mirrored the progression of retinal degeneration (Fig. 1b)
We found that the mir-125b signal was present in the outer plexiform layer (OPL), inner nuclear layer (INL) and ganglion cell layer (GCL), and was co-localized with PKCα, which suggested that rod bipolar cells (RBCs) could be miR-125b-5p positive (Fig. 3c)
Summary
Retinitis pigmentosa (RP) is a form of inherited retinal degeneration that causes blindness in humans, due to a progressive loss of photoreceptors. A previous study from our group has shown that, during retinal degeneration in RCS rats, ectopic dendrites from rod bipolar cells (RBCs) extend into the outer nuclear layer (ONL)[3]. A large pool of different miRNA is expressed in post-mitotic neurons at times of synapse development, and many of these miRNAs are associated with translation regulatory complexes[7, 8]. We hypothesized that miRNAs associated with RP might be involved with the regulation of RBC ectopic neuritogenesis during retinal degeneration. In this study of RCS rats, we used miRNA microarray technology to show that miR-125b-5p was associated with retinal degeneration, and that it regulated dendritic growth and function in RBCs. This work provides proof-of-concept for the potential treatment of retinal degeneration by knockdown of miR-125b-5p
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