Abstract
Deafferentation results not only in sensory loss, but also in a variety of alterations in the postsynaptic circuitry. These alterations may have detrimental impact on potential treatment strategies. Progressive loss of photoreceptors in retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration, leads to several changes in the remnant retinal circuitry. Müller glial cells undergo hypertrophy and form a glial seal. The second- and third-order retinal neurons undergo morphological, biochemical and physiological alterations. A result of these alterations is that retinal ganglion cells (RGCs), the output neurons of the retina, become hyperactive and exhibit spontaneous, oscillatory bursts of spikes. This aberrant electrical activity degrades the signal-to-noise ratio in RGC responses, and thus the quality of information they transmit to the brain. These changes in the remnant retina, collectively termed “retinal remodeling”, pose challenges for genetic, cellular and bionic approaches to restore vision. It is therefore crucial to understand the nature of retinal remodeling, how it affects the ability of remnant retina to respond to novel therapeutic strategies, and how to ameliorate its effects. In this article, we discuss these topics, and suggest that the pathological state of the retinal output following photoreceptor loss is reversible, and therefore, amenable to restorative strategies.
Highlights
Loss of photoreceptors, as in retinitis pigmentosa and age-related macular degeneration, leads to extensive, phased, and regressive remodeling in inner retina (Strettoi and Pignatelli, 2000; Marc et al, 2003; Cuenca et al, 2005; Gargini et al, 2007; Barhoum et al, 2008; Nagar et al, 2009)
A photoswitch expressed with light-gated ionotropic glutamate receptor (LiGluR) in retinal ganglion cells (RGCs) or ON bipolar cells has been shown to restore vision in mice and canine models of retinal degeneration (Caporale et al, 2011; Gaub et al, 2014)
Specific cells can be sorted by FACS, and their transcriptome analyzed by RNA sequencing during or following photoreceptor degeneration; this could help identify the signaling molecules and pathways involved in remodeling, and potentially help discover novel interventional strategies (Sharma et al, 2015; Yang et al, 2015)
Summary
As in retinitis pigmentosa and age-related macular degeneration, leads to extensive, phased, and regressive remodeling in inner retina (Strettoi and Pignatelli, 2000; Marc et al, 2003; Cuenca et al, 2005; Gargini et al, 2007; Barhoum et al, 2008; Nagar et al, 2009). Some of the retinal neurotransmitter receptors, such as type-6 metabotropic glutamate receptors (mGluR6) and GABAC receptors are downregulated, whereas others, such as AMPA, GABAA, and glycine receptors are upregulated following photoreceptor loss (Varela et al, 2003; Marc et al, 2007; Chua et al, 2009; Puthussery et al, 2009; Srivastava et al, 2015). The synaptic proteins in bipolar cells and amacrine cells (ACs) are upregulated, suggesting increased synaptic activity in these cell (Margolis et al, 2008; Borowska et al, 2011; Margolis and Detwiler, 2011; Dagar et al, 2014; Figure 1A)
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