Neuroprotective effects of all-trans-retinoic acid are mediated via downregulation of TLR4/NF-κB signaling in a rat model of middle cerebral artery occlusion.

OBJECTIVES: To determine the effects of all-trans-retinoic acid (ATRA) on the post-stroke inflammatory response and elucidate the underlying molecular mechanisms. METHODS: This animal experiment was conducted at Central Laboratory, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China during 2020-2022. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h, and treated with ATRA at 2 and 24 h after reperfusion. Neurological deficit scores on behavioral tests, and cerebral infarct volume, microglial polarization, and the expression levels of inflammatory cytokines and proteins associated with TLR4/NF-κB signaling were assessed. RESULTS: The ATRA administration reduced cerebral infarct volume and ameliorated neurological deficit scores in MCAO rats. Additionally, ATRA relieved cerebral edema and downregulated the secretion of proinflammatory cytokines after stroke. Finally, ATRA attenuated the polarization of the microglia toward the M1 phenotype and promoted the activation of the beneficial M2 phenotype; the underlying mechanism potentially involved the suppression of the TLR4/NF-κB signaling pathway. CONCLUSION: The ATRA treatment promoted functional recovery in an experimental model of ischemic stroke by attenuating neural inflammation. ATRA potentially modulated microglia-mediated neuroinflammation via the downregulation of the TLR4/NF-κB signaling pathway, which makes it a candidate treatment for post-stroke neuroinflammation.

Enhancing Retinoic Acid-mediated Effects Through Inhibition of CYP26A1, CYP26B1 and HGF Signaling in Neuroblastoma Cells.

BACKGROUND/AIM: Retinoic acid (RA) induces tumor cell differentiation in diseases like acute promyelocytic leukemia or high-risk neuroblastoma. However, the formation of resistant cells, which results from dysregulation of different signaling pathways, limits therapy success. The present study aimed to characterize basic regulatory processes induced by the application of RA in human neuroblastoma cells, to identify therapeutic targets independent of the often amplified oncogene MYCN. MATERIALS AND METHODS: In MYCN-amplified Kelly and MYCN non-amplified SH-SY5Y cells, different assays were employed to quantify the viability and cytotoxicity, while RA-mediated expression changes were examined using genome-wide gene expression analysis followed by quantitative PCR. Enzyme-linked immunoabsorbent assays (ELISA) and western blots were used to determine the levels or activation of the examined proteins. RESULTS: In Kelly cells, treatment with 5 µM RA for 3 days significantly reduced the cell number due to attenuated proliferation, while SH-SY5Y cells were less responsive. An up-regulation of the RA-metabolizing enzymes CYP26A1 and CYP26B1 was observed in both cell lines, and co-treatment with the selective CYP26 inhibitor talarozole markedly decreased cell viability. When RA and ketoconazole, which inhibits CYP26 as well as RA-degrading CYP3A enzymes, were co-administered, not only cell survival was impaired in both cell lines, but also the release of hepatocyte growth factor (HGF). Accordingly, co-application of the c-Met inhibitor tepotinib and RA or ketoconazole substantially decreased cell viability. CONCLUSION: Independent of MYCN amplification, inhibitors of RA metabolism or HGF signaling might prevent the emergence of RA-resistant neuroblastoma cells when co-applied with RA.

Analysis of the mechanisms underlying the anticancer and biological activity of retinoic acid and chitosan nanoparticles containing retinoic acid.

Retinoic acid (RA) has been shown in earlier investigations to have anticancer properties in various cancer cells. RA's effect on breast cancer treatment remains uncertain, though. This study investigated whether RA and chitosan nanoparticles (NPs) loaded with RA could be harmful to the MCF-7 cell line. In this study, NPs with RA were used in characterization tests. Using ELISA kits, the amounts of 8-okso-2'-deoksiguanozin (8-oxo-dG), BCL-2, Bcl-2-Associated X-protein (Bax), cleaved Poly (ADP-ribose) polymerases (PARP), total oxidant and antioxidant, and cleaved caspase-3 capacities were determined. The analysis of chitosan NPs showed that their drug-release profile, encapsulation efficiency (EE), and particle size were suitable for cell culture experiment. The EE value of NPs including RA was calculated as 83.32 ± 0.04%. The IC50 value for RA was 2.89 ± 0.03 µg/mL, while the IC50 value for RA-loaded NPs was significantly lower at 2.28 ± 0.02 µg/mL. In ELISA testing, RA and chitosan NPs containing RA at a concentration of 2 µg/mL dramatically increased the concentrations of total oxidant, cleaved caspase-3. Cleaved caspase-3 levels were quantified as 614.90 ± 3.40 pg/mg protein in the control group, 826.37 ± 5.82 pg/mg protein in RA-treated cells, and 863.52 ± 4.32 pg/mg protein in RA-NP-treated cells. Interestingly, no substantial variations were observed in the levels of the anti-apoptotic protein BCL-2. Overall, studies revealed that RA and RA-NPs promoted apoptosis in MCF-7 cells by upregulating the expression of pro-apoptotic proteins Bax, cleaved caspase-3, and cleaved PARP.

Keratin 8/18a.1 Expression Influences Embryonic Neural Crest Cell Dynamics and Contributes to Postnatal Corneal Regeneration in Zebrafish.

A complete understanding of neural crest cell mechanodynamics during ocular development will provide insight into postnatal neural crest cell contributions to ophthalmic abnormalities in adult tissues and inform regenerative strategies toward injury repair. Herein, single-cell RNA sequencing in zebrafish during early eye development revealed keratin intermediate filament genes krt8 and krt18a.1 as additional factors expressed during anterior segment development. In situ hybridization and immunofluorescence microscopy confirmed krt8 and krt18a.1 expression in the early neural plate border and migrating cranial neural crest cells. Morpholino oligonucleotide (MO)-mediated knockdown of K8 and K18a.1 markedly disrupted the migration of neural crest cell subpopulations and decreased neural crest cell marker gene expression in the craniofacial region and eye at 48 h postfertilization (hpf), resulting in severe phenotypic defects reminiscent of neurocristopathies. Interestingly, the expression of K18a.1, but not K8, is regulated by retinoic acid (RA) during early-stage development. Further, both keratin proteins were detected during postnatal corneal regeneration in adult zebrafish. Altogether, we demonstrated that both K8 and K18a.1 contribute to the early development and postnatal repair of neural crest cell-derived ocular tissues.

Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development.

The development of functional neurons is a complex orchestration of multiple signaling pathways controlling cell proliferation and differentiation. Because the balance of antioxidants is important for neuronal survival and development, we hypothesized that ferroptosis must be suppressed to gain neurons. We find that removal of antioxidants diminishes neuronal development and laminar organization of cortical organoids, which is fully restored when ferroptosis is inhibited by ferrostatin-1 or when neuronal differentiation occurs in the presence of vitamin A. Furthermore, iron-overload-induced developmental growth defects in C. elegans are ameliorated by vitamin E and A. We determine that all-trans retinoic acid activates the Retinoic Acid Receptor, which orchestrates the expression of anti-ferroptotic genes. In contrast, retinal and retinol show radical-trapping antioxidant activity. Together, our study reveals an unexpected function of vitamin A in coordinating the expression of essential cellular gatekeepers of ferroptosis, and demonstrates that suppression of ferroptosis by radical-trapping antioxidants or by vitamin A is required to obtain mature neurons and proper laminar organization in cortical organoids.

From iPSCs to Pancreatic ß Cells: Unveiling Molecular Pathways and Enhancements with Vitamin C and Retinoic Acid in Diabetes Research.

Diabetes mellitus, a chronic and non-transmissible disease, triggers a wide range of micro- and macrovascular complications. The differentiation of pancreatic ß-like cells (PßLCs) from induced pluripotent stem cells (iPSCs) offers a promising avenue for regenerative medicine aimed at treating diabetes. Current differentiation protocols strive to emulate pancreatic embryonic development by utilizing cytokines and small molecules at specific doses to activate and inhibit distinct molecular signaling pathways, directing the differentiation of iPSCs into pancreatic ß cells. Despite significant progress and improved protocols, the full spectrum of molecular signaling pathways governing pancreatic development and the physiological characteristics of the differentiated cells are not yet fully understood. Here, we report a specific combination of cofactors and small molecules that successfully differentiate iPSCs into PßLCs. Our protocol has shown to be effective, with the resulting cells exhibiting key functional properties of pancreatic ß cells, including the expression of crucial molecular markers (pdx1, nkx6.1, ngn3) and the capability to secrete insulin in response to glucose. Furthermore, the addition of vitamin C and retinoic acid in the final stages of differentiation led to the overexpression of specific ß cell genes.

Leveraging adrenergic receptor blockade for enhanced nonalcoholic fatty liver disease treatment via a biomimetic nanoplatform.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation, steatosis and fibrosis. Sympathetic nerves play a critical role in maintaining hepatic lipid homeostasis and regulating fibrotic progression through adrenergic receptors expressed by hepatocytes and hepatic stellate cells; however, the use of sympathetic nerve-focused strategies for the treatment of NAFLD is still in the infancy. Herein, a biomimetic nanoplatform with ROS-responsive and ROS-scavenging properties was developed for the codelivery of retinoic acid (RA) and the adrenoceptor antagonist labetalol (LA). The nanoplatform exhibited improved accumulation and sufficient drug release in the fibrotic liver, thereby achieving precise codelivery of drugs. Integration of adrenergic blockade effectively interrupted the vicious cycle of sympathetic nerves with hepatic stellate cells (HSCs) and hepatocytes, which not only combined with RA to restore HSCs to a quiescent state but also helped to reduce hepatic lipid accumulation. We demonstrated the excellent ability of the biomimetic nanoplatform to ameliorate liver inflammation, fibrosis and steatosis. Our work highlights the tremendous potential of a sympathetic nerve-focused strategy for the management of NAFLD and provides a promising nanoplatform for the treatment of NAFLD.

Considerations for Using Neuroblastoma Cell Lines to Examine the Roles of Iron and Ferroptosis in Neurodegeneration.

Ferroptosis is an iron-dependent form of programmed cell death that is influenced by biological processes such as iron metabolism and senescence. As brain iron levels increase with aging, ferroptosis is also implicated in the development of age-related pathologic conditions such as Alzheimer's disease (AD) and related dementias (ADRD). Indeed, inhibitors of ferroptosis have been shown to be protective in models of degenerative brain disorders like AD/ADRD. Given the inaccessibility of the living human brain for metabolic studies, the goal of this work was to characterize an in vitro model for understanding how aging and iron availability influence neuronal iron metabolism and ferroptosis. First, the human (SH-SY5Y) and mouse (Neuro-2a) neuroblastoma lines were terminally differentiated into mature neurons by culturing in all-trans-retinoic acid for at least 72 h. Despite demonstrating all signs of neuronal differentiation and maturation, including increased expression of the iron storage protein ferritin, we discovered that differentiation conferred ferroptosis resistance in both cell lines. Gene expression data indicates differentiated neurons increase their capacity to protect against iron-mediated oxidative damage by augmenting cystine import, and subsequently increasing intracellular cysteine levels, to promote glutathione production and glutathione peroxidase activity (GPX). In support of this hypothesis, we found that culturing differentiated neurons in cysteine-depleted media sensitized them to GPX4 inhibition, and that these effects are mitigated by cystine supplementation. Such findings are important as they provide guidance for the use of in vitro experimental models to investigate the role of ferroptosis in neurodegeneration in pathologies such as ADRD.

Tuning RXR Modulators for PGC1α Recruitment.

The molecular activation mechanism of the nuclear retinoid X receptors (RXRs) crucially involves ligand-induced corepressor release and coactivator recruitment which mediate transcriptional repression or activation. The ability of RXR to bind diverse coactivators suggests that a coregulator-selective modulation by ligands may open an avenue to tissue- or gene-selective RXR activation. Here, we identified strong induction of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) binding to RXR by a synthetic agonist but not by the endogenous ligand 9-cis retinoic acid. Structure-guided diversification of this lead resulted in a set of three structurally related RXR agonists with different ability to promote PGC1α recruitment in cell-free and cellular context. These results demonstrate that selective modulation of coregulator recruitment to RXR can be achieved with molecular glues and potentially open new therapeutic opportunities by targeting the ligand-induced RXR-PGC1α interaction.

Retinoic acid, an essential component of the roof plate organizer, promotes the spatiotemporal segregation of dorsal neural fates.

Dorsal neural tube-derived retinoic acid promotes the end of neural crest production and transition into a definitive roof plate. Here, we analyze how this impacts the segregation of central and peripheral lineages, a process essential for tissue patterning and function. Localized in ovo inhibition in quail embryos of retinoic acid activity followed by single-cell transcriptomics unraveled a comprehensive list of differentially expressed genes relevant to these processes. Importantly, progenitors co-expressed neural crest, roof plate and dI1 interneuron markers, indicating a failure in proper lineage segregation. Furthermore, separation between roof plate and dI1 interneurons is mediated by Notch activity downstream of retinoic acid, highlighting their crucial role in establishing the roof plate-dI1 boundary. Within the peripheral branch, where absence of retinoic acid resulted in neural crest production and emigration extending into the roof plate stage, sensory progenitors failed to separate from melanocytes, leading to formation of a common glia-melanocyte cell with aberrant migratory patterns. In summary, the implementation of single-cell RNA sequencing facilitated the discovery and characterization of a molecular mechanism responsible for the segregation of dorsal neural fates during development.

Quantitative analysis of cis-regulatory elements in transcription with KAS-ATAC-seq.

Cis-regulatory elements (CREs) are pivotal in orchestrating gene expression throughout diverse biological systems. Accurate identification and in-depth characterization of functional CREs are crucial for decoding gene regulation networks during cellular processes. In this study, we develop Kethoxal-Assisted Single-stranded DNA Assay for Transposase-Accessible Chromatin with Sequencing (KAS-ATAC-seq) to quantitatively analyze the transcriptional activity of CREs. A main advantage of KAS-ATAC-seq lies in its precise measurement of ssDNA levels within both proximal and distal ATAC-seq peaks, enabling the identification of transcriptional regulatory sequences. This feature is particularly adept at defining Single-Stranded Transcribing Enhancers (SSTEs). SSTEs are highly enriched with nascent RNAs and specific transcription factors (TFs) binding sites that define cellular identity. Moreover, KAS-ATAC-seq provides a detailed characterization and functional implications of various SSTE subtypes. Our analysis of CREs during mouse neural differentiation demonstrates that KAS-ATAC-seq can effectively identify immediate-early activated CREs in response to retinoic acid (RA) treatment. Our findings indicate that KAS-ATAC-seq provides more precise annotation of functional CREs in transcription. Future applications of KAS-ATAC-seq would help elucidate the intricate dynamics of gene regulation in diverse biological processes.

Individual variation in the emergence of anterior-to-posterior neural fates from human pluripotent stem cells.

Variability between human pluripotent stem cell (hPSC) lines remains a challenge and opportunity in biomedicine. In this study, hPSC lines from multiple donors were differentiated toward neuroectoderm and mesendoderm lineages. We revealed dynamic transcriptomic patterns that delineate the emergence of these lineages, which were conserved across lines, along with individual line-specific transcriptional signatures that were invariant throughout differentiation. These transcriptomic signatures predicted an antagonism between SOX21-driven forebrain fates and retinoic acid-induced hindbrain fates. Replicate lines and paired adult tissue demonstrated the stability of these line-specific transcriptomic traits. We show that this transcriptomic variation in lineage bias had both genetic and epigenetic origins, aligned with the anterior-to-posterior structure of early mammalian development, and was present across a large collection of hPSC lines. These findings contribute to developing systematic analyses of PSCs to define the origin and consequences of variation in the early events orchestrating individual human development.

Dynamic upregulation of retinoic acid signal in the early postnatal murine heart promotes cardiomyocyte cell cycle exit and maturation.

The adult mammalian heart has extremely limited cardiac regenerative capacity. Most cardiomyocytes live in a state of permanent cell-cycle arrest and are unable to re-enter the cycle. Cardiomyocytes switch from cell proliferation to a maturation state during neonatal development. Although several signaling pathways are involved in this transition, the molecular mechanisms by which these inputs coordinately regulate cardiomyocyte maturation are not fully understood. Retinoic acid (RA) plays a pivotal role in development, morphogenesis, and regeneration. Despite the importance of RA signaling in embryo heart development, little is known about its function in the early postnatal period. We found that mRNA expression of aldehyde dehydrogenase 1 family member A2 (Aldh1a2), which encodes the key enzyme for synthesizing all-trans retinoic acid (ATRA) and is an important regulator for RA signaling, was transiently upregulated in neonatal mouse ventricles. Single-cell transcriptome analysis and immunohistochemistry revealed that Aldh1a2 expression was enriched in cardiac fibroblasts during the early postnatal period. Administration of ATRA inhibited cardiomyocyte proliferation in cultured neonatal rat cardiomyocytes and human cardiomyocytes. RNA-seq analysis indicated that cell proliferation-related genes were downregulated in prenatal rat ventricular cardiomyocytes treated with ATRA, while cardiomyocyte maturation-related genes were upregulated. These findings suggest that RA signaling derived from cardiac fibroblasts is one of the key regulators of cardiomyocyte proliferation and maturation during neonatal heart development.

Transglutaminase 2 Regulates HSF1 Gene Expression in the Acute Phase of Fish Optic Nerve Regeneration.

Fish retinal ganglion cells (RGCs) can regenerate after optic nerve lesions (ONLs). We previously reported that heat shock factor 1 (HSF1) and Yamanaka factors increased in the zebrafish retina 0.5-24 h after ONLs, and they led to cell survival and the transformation of neuro-stem cells. We also showed that retinoic acid (RA) signaling and transglutaminase 2 (TG2) were activated in the fish retina, performing neurite outgrowth 5-30 days after ONLs. In this study, we found that RA signaling and TG2 increased within 0.5 h in the zebrafish retina after ONLs. We examined their interaction with the TG2-specific morpholino and inhibitor due to the significantly close initiation time of TG2 and HSF1. The inhibition of TG2 led to the complete suppression of HSF1 expression. Furthermore, the results of a ChIP assay with an anti-TG2 antibody evidenced significant anti-TG2 immunoprecipitation of HSF1 genome DNA after ONLs. The inhibition of TG2 also suppressed Yamanaka factors' gene expression. This rapid increase in TG2 expression occurred 30 min after the ONLs, and RA signaling occurred 15 min before this change. The present study demonstrates that TG2 regulates Yamanaka factors via HSF1 signals in the acute phase of fish optic nerve regeneration.

The Interplay of Carveol and All-Trans Retinoic Acid (ATRA) in Experimental Parkinson's Disease: Role of Inflammasome-Mediated Pyroptosis and Nrf2.

Parkinson's disease (PD) is a debilitating and the second most common neurodegenerative disorder with a high prevalence. PD has a multifaceted etiology characterized by an altered redox state and an excessive inflammatory response. Extensive research has consistently demonstrated the role of the nuclear factor E2-related factor (Nrf2) and inflammasomes, notably NLRP3 in neurodegenerative diseases. In this study, our focus was on exploring the potential neuroprotective properties of carveol in Parkinson's disease. Our findings suggest that carveol may exhibit these effects through Nrf2 and by suppressing pyroptosis. Male albino mice were treated with carveol, and the animal PD model was induced through a single intranigral dose of 2 µg/2µl lipopolysaccharide (LPS). To further demonstrate the essential role of the Nrf2 pathway, we utilized all-trans retinoic acid (ATRA) to inhibit the Nrf2. Our finding showed the induction of pyroptosis as evidenced by increased levels of NLRP3 and other inflammatory mediators, including IL-1ß, iNOS, p-NFKB, and apoptotic cell death indicated by positive fluoro Jade B (FJB) staining. Moreover, increased levels of lipid peroxides and reactive oxygen species indicated a significant rise in oxidative stress due to LPS. The administration of carveol mitigates oxidative stress and suppresses inflammatory pathways through the augmentation of intrinsic antioxidant defenses, primarily via the activation of the Nrf2. Conversely, ATRA reversed carveol protective effects by increasing FJB-positive cells, inflammatory and oxidative biomarkers. Taken together, our findings suggest that carveol mitigated LPS-induced Parkinson-like symptoms, partially through the activation of the Nrf2 and downregulation of pyroptosis notably NLRP3.

Transcriptional and epigenetic characterization of a new in vitro platform to model the formation of human pharyngeal endoderm.

BACKGROUND: The Pharyngeal Endoderm (PE) is an extremely relevant developmental tissue, serving as the progenitor for the esophagus, parathyroids, thyroids, lungs, and thymus. While several studies have highlighted the importance of PE cells, a detailed transcriptional and epigenetic characterization of this important developmental stage is still missing, especially in humans, due to technical and ethical constraints pertaining to its early formation. RESULTS: Here we fill this knowledge gap by developing an in vitro protocol for the derivation of PE-like cells from human Embryonic Stem Cells (hESCs) and by providing an integrated multi-omics characterization. Our PE-like cells robustly express PE markers and are transcriptionally homogenous and similar to in vivo mouse PE cells. In addition, we define their epigenetic landscape and dynamic changes in response to Retinoic Acid by combining ATAC-Seq and ChIP-Seq of histone modifications. The integration of multiple high-throughput datasets leads to the identification of new putative regulatory regions and to the inference of a Retinoic Acid-centered transcription factor network orchestrating the development of PE-like cells. CONCLUSIONS: By combining hESCs differentiation with computational genomics, our work reveals the epigenetic dynamics that occur during human PE differentiation, providing a solid resource and foundation for research focused on the development of PE derivatives and the modeling of their developmental defects in genetic syndromes.

Rapid and efficient generation of mature retinal organoids derived from human pluripotent stem cells via optimized pharmacological modulation of Sonic hedgehog, activin A, and retinoic acid signal transduction.

Human retinal organoids have become indispensable tools for retinal disease modeling and drug screening. Despite its versatile applications, the long timeframe for their differentiation and maturation limits the throughput of such research. Here, we successfully shortened this timeframe by accelerating human retinal organoid development using unique pharmacological approaches. Our method comprised three key steps: 1) a modified self-formed ectodermal autonomous multizone (SEAM) method, including dual SMAD inhibition and bone morphogenetic protein 4 treatment, for initial neural retinal induction; 2) the concurrent use of a Sonic hedgehog agonist SAG, activin A, and all-trans retinoic acid for rapid retinal cell specification; and 3) switching to SAG treatment alone for robust retinal maturation and lamination. The generated retinal organoids preserved typical morphological features of mature retinal organoids, including hair-like surface structures and well-organized outer layers. These features were substantiated by the spatial immunostaining patterns of several retinal cell markers, including rhodopsin and L/M opsin expression in the outermost layer, which was accompanied by reduced ectopic cone photoreceptor generation. Importantly, our method required only 90 days for retinal organoid maturation, which is approximately two-thirds the time necessary for other conventional methods. These results indicate that thoroughly optimized pharmacological interventions play a pivotal role in rapid and precise photoreceptor development during human retinal organoid differentiation and maturation. Thus, our present method may expedite human retinal organoid research, eventually contributing to the development of better treatment options for various degenerative retinal diseases.

Rapid retinoic acid-induced trophoblast cell model from human induced pluripotent stem cells.

A limited number of accessible and representative models of human trophoblast cells currently exist for the study of placentation. Current stem cell models involve either a transition through a naïve stem cell state or precise dynamic control of multiple growth factors and small-molecule cues. Here, we demonstrated that a simple five-day treatment of human induced pluripotent stem cells with two small molecules, retinoic acid (RA) and Wnt agonist CHIR 99021 (CHIR), resulted in rapid, synergistic upregulation of CDX2. Transcriptomic analysis of RA + CHIR-treated cells showed high similarity to primary trophectoderm cells. Multipotency was verified via further differentiation towards cells with syncytiotrophoblast or extravillous trophoblast features. RA + CHIR-treated cells were also assessed for the established criteria defining a trophoblast cell model, and they possess all the features necessary to be considered valid. Collectively, our data demonstrate a facile, scalable method for generating functional trophoblast-like cells in vitro to better understand the placenta.

Retinoic Acid-Dependent Loss of Synaptic Output from Bipolar Cells Impairs Visual Information Processing in Inherited Retinal Degeneration.

In retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel has remained unknown. Here we report that synaptic output from BCs plummets in RP mouse models of both sexes owing to loss of voltage-gated Ca2+ channels. Remodeling reduces the reliability of synaptic output to repeated optogenetic stimuli, causing RGC firing to fail at high-stimulus frequencies. Fortunately, functional remodeling of BCs can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated either by surviving photoreceptors or by vision-restoring tools.