Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision

Abstract

Adiponectin receptor 1 (ADIPOR1) is a lipid and glucose metabolism regulator that possesses intrinsic ceramidase activity. Mutations of the ADIPOR1 gene have been associated with non-syndromic and syndromic retinitis pigmentosa. Here we show that the absence of AdipoR1 in mice leads to progressive photoreceptor degeneration, significant reduction of electroretinogram amplitudes, decreased retinoid content in the retina, and reduced cone opsin expression. Single-cell RNA-Seq results indicated that ADIPOR1 encodes the most abundantly expressed ceramidase in mice and one of the two most highly expressed ceramidases in the human retina, next to acid ceramidase ASAH1. We discovered an accumulation of ceramides in the AdipoR1 -/retina, likely due to insufficient ceramidase activity for healthy retina function, resulting in photoreceptor death. Combined treatment with desipramine and L-cycloserine (DC) lowered ceramide levels and exerted a protective effect on photoreceptors in AdipoR1 -/mice. Moreover, we observed improvement in cone-mediated retinal function in the DC-treated animals. Lastly, we found that prolonged DC-treatment corrected the electrical responses of the primary visual cortex to visual stimuli, approaching near-normal levels for some parameters.These results highlight the importance of ADIPOR1 ceramidase in the retina, and show that pharmacological inhibition of ceramide generation can provide a therapeutic strategy for ADIPOR1-related retinopathy.

Visual System Hyperexcitability and Compromised V1 Receptive Field Properties in Early-Stage Retinitis Pigmentosa in Mice

“…The LFP from multiple locations was bandpass filtered from 0.1 to 250 Hz and stored together with spiking data on a computer with a 1-kHz sampling rate. The LFP signal was cut according to stimulus time stamps and averaged across trials for each recording location to calculate visually evoked potentials (VEPs; Foik et al, 2015 ; Kordecka et al, 2020 ; Suh et al, 2020 ; Lewandowski et al, 2022 ). The spike signal was bandpass filtered from 500 Hz to 7 kHz and stored in a computer hard drive at a 30-kHz sampling frequency.…”

“…This was followed by testing contrast. Single units were recorded along the whole depth of the primary visual cortex (V1) as presented in previous studies ( Foik et al, 2018 ; Suh et al, 2020 ; Frankowski et al, 2021 ; Choi et al, 2022 ; Lewandowski et al, 2022 ).…”

Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice

“…The local field potential (LFP) from multiple locations was bandpass filtered from 0.1 Hz to 250 Hz and stored together with spiking data on a computer with a 1 kHz sampling rate. The LFP signal was cut according to stimulus time stamps and averaged across trials for each recording location to calculate visually evoked potentials (VEP) (Foik et al, 2015;Kordecka et al, 2020;Suh et al, 2020;Lewandowski et al, 2022). The spike signal was bandpass filtered from 500 Hz to 7 kHz and stored in a computer hard drive at a 30 kHz sampling frequency.…”

“…This was followed by testing contrast. Single units were recorded along the whole depth of the primary visual cortex as presented in previous studies (Foik et al, 2018;Suh et al, 2020;Frankowski et al, 2021;Choi et al, 2022;Lewandowski et al, 2022).…”

Screening of Prognostic Biomarkers for Stereotactic Body Radiation Therapy in Primary Liver Cancer

“…The activation of ADIPOR1 plays an important role in regulating glucose metabolism and fatty acid catabolism. 18 High-fat alcoholic diet downregulated the protein levels of hepatic ADIPOR1. 19 In recent years, it has been found that ADIPOR1 also plays an important role in tumorigenesis, invasion, and metastasis.…”