Mature Retina Compensates Functionally for Partial Loss of Rod Photoreceptors

Abstract

SUMMARY Loss of primary neuronal inputs inevitably strikes every neural circuit. The deafferented circuit could propagate, amplify, or mitigate input loss, thus affecting the circuit’s output. How the deafferented circuit contributes to the effect on the output is poorly understood because of lack of control over loss of and access to circuit elements. Here, we control the timing and degree of rod photoreceptor ablation in mature mouse retina and uncover compensation. Following loss of half of the rods, rod bipolar cells mitigate the loss by preserving voltage output. Such mitigation allows partial recovery of ganglion cell responses. We conclude that rod death is compensated for in the circuit because ganglion cell responses to stimulation of half of the rods in an unperturbed circuit are weaker than responses after death of half of the rods. The dominant mechanism of such compensation includes homeostatic regulation of inhibition to balance the loss of excitation.

Homeostatic plasticity in the retina is associated with maintenance of night vision during retinal degenerative disease

“…We detected fewer mGluR6 positive puncta, reflecting a decreased number of synapses, in 1-month-old P23H retinas ( Figure 2 ), and on the other hand, rod bipolar cell labeling showed indistinguishable staining patterns between P23H and control retinas ( Figure 1—figure supplement 1 ). In line with this, ablation of ~50% of rods in a WT adult mouse retina, phenotypically mimicking the situation in young adult P23H mice including compensation of the ERG b-wave amplitude, did not lead to morphological synaptic changes in the study by Care et al, 2020 . Our RNA-seq data show upregulations in a number of mRNAs of ion channels and G protein-coupled receptors, such as the Trpm1 cation channel crucial for ON bipolar cell depolarization as well as glutamatergic receptors that could contribute either to the strengthening of individual rod-rod bipolar cell synapses or increased excitability of the rod bipolar cells ( Figure 3—figure supplements 3 – 5 ).…”

“…Recent studies using the specific deletion of ~50–90% of rods, cones or rod bipolar cells during development or in mature mice have revealed homeostatic mechanisms associated with the maintenance of normal retinal output and vision ( Care et al, 2020 ; Care et al, 2019 ; Johnson et al, 2017 ; Shen et al, 2020 ; Tien et al, 2017 ). Here we used a P23H knock-in mouse model of RP that recapitulates the human disease.…”

“…rod and cone photoreceptor cells) either within their normal territory or sometimes outside of their normal dendritic field to compensate for the reduced number of photoreceptor cells. On the other hand, the most recent of such studies showed functional compensation without any observable anatomical changes in rod bipolar cells even after ablation of ~50% of rods in adult mice ( Care et al, 2020 ). These homeostatic changes could help maintain retinal output and vision at or near normal levels.…”

Pupillary reflex and behavioral masking responses to light as functional measures of retinal degeneration in mice

“…Rod/cone degeneration does lead to plastic changes in the retina [38,39]. For example, rod to rod bipolar cell signaling is potentiated in rod photoreceptor degeneration, preserving voltage output and scotopic vision [40,41]. Although speculative, it seems likely that the negative masking and PLR phenotypes, in part, reflect plastic changes in retinal cells and circuits.…”

Circadian Rhythm Disruption Results in Visual Dysfunction

“…These rod or cone bipolar dendrites may extend their arbors and form new synapses to compensate for a reduced number of photoreceptor cells (21). A recent study also reported functional compensation in the retina after ablation of 50% of rods, without any observable anatomical changes in the bipolar cells (22). We believe these homeostatic mechanisms may have also contributed to rescuing photopic ERG in the entrained mice in spite of a significant reduction in cone photoreceptor numbers.…”