Retinoic acid inhibitors mitigate vision loss in a mouse model of retinal degeneration

Abstract

Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca 2+ imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes. An RA receptor inhibitor also reduces RGC hyperactivity, sharpens cortical representations, and improves image detection. These findings suggest that photoreceptor degeneration is not the only cause of vision loss in RP. RA-induced corruption of retinal information processing also degrades vision, pointing to RA synthesis and signaling inhibitors as potential therapeutic tools for improving sight in RP and other retinal degenerative disorders.

Genome-wide analyses identify novel risk loci for cluster headache in Han Chinese residing in Taiwan

“…In addition, both GWAS and gene-based association analysis suggested CYP2C18 as a potential novel susceptibility gene for cluster headache. Interesting, CYP2C18 is a cytochrome P450 monooxygenase involved in retinoid metabolism [ 49 ], while retinoic acid is a molecular trigger of RGC hyperactivity [ 50 ]. Taken together, the top implicated genes in our study may modulate the function of RGCs; however, how this could be involved in cluster headache pathogenesis particularly circadian rhythmicity requires further validation.…”

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina

“…Briefly, aberrant gap junction coupling maybe present in the outer retina, but gap junction coupling in the inner AII Amacrine On-Cone Bipolar cell (AII-CBC) network is likely unchanged (Borowska et al, 2011;Trenholm et al, 2012;Menzler et al, 2014). A few reports also support abnormal gap junction coupling between RGCs as a locus for spontaneous activity (Telias et al, 2019(Telias et al, , 2022Denlinger et al, 2020). To examine what changes may be involved in driving correlations in spontaneous activity, we first confirmed that spontaneous activity and synchronized activity are eliminated when gap junctions are blocked.…”

“…Briefly, aberrant gap junction coupling maybe present in the outer retina, but gap junction coupling in the inner AII Amacrine On-Cone Bipolar cell (AII-CBC) network is likely unchanged ( Borowska et al, 2011 ; Trenholm et al, 2012 ; Menzler et al, 2014 ). A few reports also support abnormal gap junction coupling between RGCs as a locus for spontaneous activity ( Telias et al, 2019 , 2022 ; Denlinger et al, 2020 ).…”

“…The definition of evoked and spontaneous activity in a spontaneously firing cell maybe somewhat semantic, although it serves to highlight the challenges associated with resolving evoked information carrying visual information, from background activity. The idea that increased spontaneous firing will decrease the signal to noise for restored visual signals has received considerable theoretical and experimental support ( Dräger and Hubel, 1978 ; Sauvé et al, 2001 ; Stasheff, 2008 , 2018 ; Toychiev et al, 2013 ; Yee et al, 2014 ; Barrett, 2015 ; Ivanova et al, 2016 ; Telias et al, 2019 , 2022 ; Ho et al, 2020 ), and to some extent the challenges that exist for experimentally separating evoked and spontaneous spikes will exist for the brain during vision restoration. Our findings show this distinction between evoked and spontaneous activity is important as they have different spatio-temporal properties and are mediated by different circuit mechanisms, and thus may be differentially targeted.…”

“…These diseases also serve as important model systems for neurodegeneration owing to the retina’s experimental tractability ( Tirassa et al, 2018 ; Trapani and Auricchio, 2018 ). Recent advances in optoelectronics have enabled high-resolution retinal prosthetics ( Ha et al, 2016 ; Yang et al, 2016 ; Bosse et al, 2018 ; Edwards et al, 2018 ; Palanker et al, 2020 ), new gene therapy strategies also show promise ( Trapani and Auricchio, 2018 ; Wood et al, 2019 ; Sahel et al, 2021 ; Cehajic-Kapetanovic et al, 2022 ), and advances in stem cell research has allowed for the transplantation of new photoreceptors ( Ludwig and Gamm, 2021 ; Ribeiro et al, 2021 ; Zerti et al, 2021 ); however, there is much concern about how disease related changes impact the fidelity of restored vision ( Dräger and Hubel, 1978 ; Sauvé et al, 2001 ; Stasheff, 2008 , 2018 ; Toychiev et al, 2013 ; Yee et al, 2014 ; Ivanova et al, 2016 ; Jones et al, 2016 ; Telias et al, 2019 , 2022 ; Zerti et al, 2021 ). Although, some interactions between disease related changes and prosthetic vision restoration have been studied in the past ( Ryu et al, 2011 ; Yee et al, 2012 ; Goo et al, 2015 ; Cho et al, 2016 ; Stutzki et al, 2016 ; Ahn et al, 2022 ), many important questions remain unresolved, such as how degeneration changes spatiotemporal processing in retinal circuitry.…”