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Subspecialties Basic & Translational Research, Retina

The Night Watch

The findings of a recent study of retinitis pigmentosa in mice could be useful in explaining why patients suffering from retinal disorders might be able to maintain their night vision. The possible mechanism? Homeostatic plasticity – when second-order neurons in the retina maintain their function even as rod photoreceptor degeneration continues.

Researchers from the University of California in Irvine and the University of Utah in Salt Lake City, USA, used whole-retina RNA sequencing, electrophysiology, and behavioral experiments to show that degeneration of rod photoreceptors causes changes to the retina at the genome level. It also increases electrical signaling between rod receptors and rod bipolar cells. An improved understanding of homeostatic plasticity of the inner retina could inform future treatments. 

Here, we speak to first author Henri Leinonen, Postdoctoral Scholar at the Palczewski Lab, Gavin Herbert Eye Institute Department of Ophthalmology, University of California, Irvine, to find out more.

How does your work build on existing research into neuronal plasticity of the inner retina?

Our study provides a novel point of view to the inner retinal plasticity and remodeling during photoreceptor degenerative disease. Traditionally, remodeling of the inner retina has been considered as a negative phenomenon that could preclude vision restoration strategies in the blind by, for instance, photoreceptor transplantation or optogenetic tools. However, very recent evidence from artificial photoreceptor-ablation models suggests that photoreceptor loss triggers homeostatic plasticity in the inner retina that is expected to promote vision. Our study conducted using a progressive Retinitis Pigmentosa model increases the concept’s translational relevance, and strongly suggests that sensory system tries to maintain basal functionality through homeostatic plasticity in early to intermediate disease state. I do believe, however, that the neural network eventually goes haywire as disease advances.

The study was conducted at a relatively early stage of disease progression; how would the age of the mice compare in terms of RP progression in humans?

Our study was conducted using an established mouse model of the autosomal dominant Retinitis Pigmentosa (RP) caused by the P23H mutation. This disease typically manifests in young adults, whereas many other RP subtypes can manifest in children. Our experiments primarily focused on mice at postnatal day 30. These mice are not sexually mature, and could roughly correspond juveniles in human lifespan. We chose to do this because the further the disease advances the more inflammation and cell stress associated with the disease complicates data interpretation, especially with respect to molecular genetics data. Nevertheless, we detected profound functional inner retina compensation to decreasing sensory receptor input even when the mice were five months of age. This could correspond to young adult humans, perhaps in their 30s.

What were the key findings that came out of the work?

Firstly, the adult mammalian retina appear to be more plastic than previously though. Secondly, defects in the sensory neurons can be, to a certain extent, be compensated downstream in the neuronal circuit. This could explain why many patients’ visual function is surprisingly well maintained regardless of profound anatomical pathology. In our case, the RP mice maintained sensitive behavioral contrast sensitivity even when over half of their rod photoreceptors were dead. Importantly, our mice were genetically engineered to lack cone photoreceptor function, so the finding cannot be explained by compensation by the cone-pathway that is known to be better preserved in most types of RP.

How might these findings impact treatment strategies for blinding diseases?

Before direct translation, we need to find out the molecular and physiological mechanisms that explain the phenomenon. This might help us designing interventions that promote plasticity when needed, and perhaps suppress it when undesirable.

Do you plan on discovering the exact mechanisms that promote cellular signalling and visual function, and if so, how?

Absolutely. That is the main point in the whole project. Not only could this be important in vision/ophthalmology research, but also in neuroscience. The eye is a wonderful model organism due to its transparency and relatively easy accessibility. We are confident that the exact mechanisms of the newly discovered phenomenon will be discovered in near future. Modern and established life science and neuroscience methods, such as single-cell RNA-sequencing and single-cell electrophysiology combined to genetic tools and pharmacology will help us in our quest.


Credit: The Night Watch by Rembrandt van Rijn, the Rijksmuseum, Amsterdam, The Netherlands.

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  1. H Leinonen et al., Elife [Epub ahead of print] (2020). PMID: 32960171.
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