80 research outputs found
Loss of HCN1 enhances disease progression in mouse models of CNG channel-linked retinitis pigmentosa and achromatopsia
No full textMost inherited blinding diseases are characterized by compromised retinal function and progressive degeneration of photoreceptors. However, the factors that affect the life span of photoreceptors in such degenerative retinal diseases are rather poorly understood. Here we explore the role of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) in this context. HCN1 is known to adjust retinal function under mesopic conditions, and although it is expressed at high levels in rod and cone photoreceptor inner segments, no association with any retinal disorder has yet been found. We investigated the effects of an additional genetic deletion of HCN1 on the function and survival of photoreceptors in a mouse model of CNGB1-linked retinitis pigmentosa (RP). We found that the absence of HCN1 in Cngb1 knockout (KO) mice exacerbated photoreceptor degeneration. The deleterious effect was reduced by expression of HCN1 using a viral vector. Moreover, pharmacological inhibition of HCN1 also enhanced rod degeneration in Cngb1 KO mice. Patch-clamp recordings revealed that the membrane potentials of Cngb1 KO and Cngb1/Hcn1 double KO rods were both significantly depolarized. We also found evidence for altered calcium homeostasis and increased activation of the protease calpain in Cngb1/Hcn1 double KO mice. Finally, the deletion of HCN1 also exacerbated degeneration of cone photoreceptors in a mouse model of CNGA3-linked achromatopsia. Our results identify HCN1 as a major modifier of photoreceptor degeneration and suggest that pharmacological inhibition of HCN channels may enhance disease progression in RP and achromatopsia patients
Candidate chemosensory cells in the stomach mucosa of young postnatal mice during the phases of dietary changes
No full text
Mosaic synaptopathy and functional defects in Cav1.4 heterozygous mice and human carriers of CSNB2
No full text
Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2
No full text
HCN1 Channels Enhance Rod System Responsivity in the Retina under Conditions of Light Exposure.
No full textVision originates in rods and cones at the outer retina. Already at these early stages, diverse processing schemes shape and enhance image information to permit perception over a wide range of lighting conditions. In this work, we address the role of hyperpolarization-activated and cyclic nucleotide-gated channels 1 (HCN1) in rod photoreceptors for the enhancement of rod system responsivity under conditions of light exposure.To isolate HCN1 channel actions in rod system responses, we generated double mutant mice by crossbreeding Hcn1-/- mice with Cnga3-/- mice in which cones are non-functional. Retinal function in the resulting Hcn1-/- Cnga3-/- animals was followed by means of electroretinography (ERG) up to the age of four month. Retinal imaging via scanning laser ophthalmoscopy (SLO) and optical coherence tomography (OCT) was also performed to exclude potential morphological alterations.This study on Hcn1-/- Cnga3-/- mutant mice complements our previous work on HCN1 channel function in the retina. We show here in a functional rod-only setting that rod responses following bright light exposure terminate without the counteraction of HCN channels much later than normal. The resulting sustained signal elevation does saturate the retinal network due to an intensity-dependent reduction in the dynamic range. In addition, the lack of rapid adaptational feedback modulation of rod photoreceptor output via HCN1 in this double mutant limits the ability to follow repetitive (flicker) stimuli, particularly under mesopic conditions.This work corroborates the hypothesis that, in the absence of HCN1-mediated feedback, the amplitude of rod signals remains at high levels for a prolonged period of time, leading to saturation of the retinal pathways. Our results demonstrate the importance of HCN1 channels for regular vision
Electroretinographic assessment of rod- and cone-mediated bipolar cell pathways using flicker stimuli in mice
No full textMouse full-field electroretinograms (ERGs) are dominated by responses of photoreceptors and depolarizing (ON-) bipolar cells, but not much of hyperpolarizing (OFF-) bipolar cells under conventional recording conditions. Here we investigate a novel ERG protocol in mice for functional assessment of the major ON-and OFF- bipolar cell pathways using flicker stimuli for a high luminance with varying frequency up to 30 Hz. Wild- type (WT) and functionally specific transgenic mice (Cnga3(-/-),no cone photoreceptor function;rho(-/-),no rod photoreceptor function;mGluR6(-/-),no ON-bipolar cell function) were examined. The Cnga3(-/-) flicker ERG was similar to the WT flicker ERG at very low stimulus frequencies, whereas ERGs were comparable between WT and rho(-/-) mice at 5 Hz and above. Between 5 and 15 Hz, ERGs in mGluR6(-/-) mice differed in configuration and amplitude from those in WT and rho(-/-) mice;in contrast, response amplitudes above 15 Hz were comparable among WT, rho(-/-) and mGluR6(-/-) mice. In summary, we found three frequency ranges with these conditions that are dominated by activity in the rod pathways (below 5 Hz),cone ON-pathway (between 5 and 15 Hz),and cone OFF-pathway (above 15 Hz) that enables a quick overview of the functionality of the major bipolar cell pathways
- …
