Biology subjects

Hottin, C.

Publications and source records attributed to Hottin, C..

3 recordsLinked to original sources

bioRxiv2026

Evidence for a rod-to-cone lactate shuttle in the mammalian retina

In his seminal 1920s studies, Otto Warburg found the retina to generate large amounts of lactate. However, it was unclear what retinal cells produced lactate and whether it was a metabolic waste product or used further. Here, we show that lactate produced by rod photoreceptors fuels the energy-intensive function and viability of cone photoreceptors. In an initial expression analysis, we found monocarboxylate transporter-1 (MCT1), lactate-producing lactate-dehydrogenase-A (LDHA), and pyruvate carboxykinase-1 (PCK1) localized to rod photoreceptors, while high-affinity MCT2, pyruvate-producing LDHB, and PCK2 were expressed in cones. We then exposed retina to defined media containing either glucose or lactate as caloric component, and applied specific MCT inhibitors. In glucose-containing medium, 1H-NMR metabolomics showed rod MCT1 inhibition to increase retinal lactate, suggesting rods as a major source of lactate. In lactate-only medium, functional recordings using micro-electroretinography showed decreased rod function, while cone function was maintained. In glucose-containing medium, blocking rod MCT1 abolished cone function. Long-term treatment with MCT inhibitors selectively decreased photoreceptor viability. Conversely, supplementing the defined medium with lactate preserved cone viability in the rd1 mouse model for Retinitis Pigmentosa. Together, our data suggest that lactate shuttling from rods is crucial for cone function and viability. This may explain cone degeneration seen in various retinal diseases and provides an entirely new avenue for metabolism-based treatment development. The discovery of a lactate-shuttle between two functionally similar, yet distinct types of neurons may have far-reaching implications for our understanding of the central nervous system in general.

neuroscience↗

bioRxiv2024

Protein kinase G inhibition preserves photoreceptor viability and function in a new mouse model for autosomal dominant retinitis pigmentosa

Retinitis Pigmentosa (RP) is the most common inherited retinal degeneration, characterized by an initial loss of rod photoreceptor cells. Photoreceptor cell death has been associated with high levels of cyclic guanosine-3', 5'-monophosphate (cGMP) in animal models of autosomal recessive RP (ARRP) and autosomal dominant RP (ADRP). cGMP analogues inhibiting protein kinase G (PKG) have been found to prevent rod degeneration in ARRP disease models, but their effects on ADRP are unknown. Here, we used the recently generated rhodopsin-mutant RhoI255d/+ ADRP mouse model to investigate cGMP-signaling and the effects of cGMP analogues targeting PKG. cGMP accumulation was investigated by retinal immunostaining in wild-type (WT), RhoI255d/+, and RhoI255d/I255d mice. The therapeutic efficacy of the cGMP analogues CN03 and CN238 was evaluated on organotypic retinal explant cultures derived from WT and RhoI255d/+ mice. Readouts included the TUNEL assay and immunostaining for cone arrestin-3. Downstream effectors of cell death were visualized using calpain, poly-ADP-ribose polymerase (PARP), and histone deacetylase (HDAC) in situ assays, as well as caspase-3 immunostaining. Photoreceptor function was assessed using micro-electroretinogram ({micro}ERG) recordings. When compared with WT, RhoI255d photoreceptors displayed cGMP accumulation in outer segments. In the RhoI255d/+ ADRP model, CN03 and CN238 significantly reduced the number of dying photoreceptors. However, the relatively small number of photoreceptors exhibiting caspase-3 activity was not changed by the treatment. Remarkably, CN238 effectively provided long-lasting neuroprotection of cone photoreceptors and preserved retinal light responsiveness of RhoI255d/+ retina. Overall, this study suggests caspase-independent but cGMP-dependent cell death as a dominant degenerative mechanism in the RhoI255d/+ ADRP mouse model. PKG inhibition demonstrated robust neuroprotection of both rod and cone photoreceptors, while the marked preservation of retinal function, especially with the compound CN238, highlighted cGMP analogues for the treatment of ADRP.

neuroscience↗

bioRxiv2021

Glycogen Synthase Kinase 3 regulates the genesis of the rare displaced ganglion cell retinal subtype

Glycogen Synthase Kinase 3 (GSK) proteins (GSK3 and GSK3{beta}) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphological defects. Both proliferation of retinal progenitors and neuronal differentiation are impaired and result in enhanced cell death. A single wild-type allele of either Gsk3 or Gsk3{beta} is able to rescue these phenotypes. In this genetic context, all cell types are present with a functional retina. However, we unexpectedly detect a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele of Gsk3 is expressed. Excess dRGCs lead to increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at least a subset of dRGCs in Gsk3 mutant mice are direction-selective RGCs. Our study thus uncovers a unique role of GSK3 in controlling the genesis of dRGCs, a rare and poorly characterized retinal cell type.

neuroscience↗