Retinal Dysfunction in a Mouse Model of HCN1 Genetic Epilepsy
| Autor: | Da Zhao, Paulo Pinares-Garcia, Chaseley E. McKenzie, Lauren E. Bleakley, Ian C. Forster, Vickie H.Y. Wong, Christine T.O. Nguyen, Ingrid E. Scheffer, Christopher A. Reid, Bang V. Bui |
|---|---|
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | The Journal of Neuroscience. 43:2199-2209 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.1615-22.2022 |
| Popis: | Pathogenic variants inHCN1are associated with a range of epilepsy syndromes including a developmental and epileptic encephalopathy. The recurrentde novo HCN1pathogenic variant (M305L) results in a cation leak, allowing the flux of excitatory ions at potentials where the wild-type channels are closed. The Hcn1M294Lmouse recapitulates patient seizure and behavioral phenotypes. As HCN1 channels are highly expressed in rod and cone photoreceptor inner segments, where they shape the light response, mutated channels are likely to impact visual function. Electroretinogram (ERG) recordings from male and female mice Hcn1M294Lmice revealed a significant decrease in the photoreceptor sensitivity to light, as well as attenuated bipolar cell (P2) and retinal ganglion cell responses. Hcn1M294Lmice also showed attenuated ERG responses to flickering lights. ERG abnormalities are consistent with the response recorded from a single female human subject. There was no impact of the variant on the structure or expression of the Hcn1 protein in the retina.In silicomodeling of photoreceptors revealed that the mutated HCN1 channel dramatically reduced light-induced hyperpolarization, resulting in more Ca2+flux during the response when compared with the wild-type situation. We propose that the light-induced change in glutamate release from photoreceptors during a stimulus will be diminished, significantly blunting the dynamic range of this response. Our data highlight the importance of HCN1 channels to retinal function and suggest that patients withHCN1pathogenic variants are likely to have a dramatically reduced sensitivity to light and a limited ability to process temporal information.SIGNIFICANCE STATEMENTPathogenic variants in HCN1 are emerging as an important cause of catastrophic epilepsy. HCN1 channels are ubiquitously expressed throughout the body, including the retina. Electroretinogram recordings from a mouse model ofHCN1genetic epilepsy showed a marked decrease in the photoreceptor sensitivity to light and a reduced ability to respond to high rates of light flicker. No morphologic deficits were noted. Simulation data suggest that the mutated HCN1 channel blunts light-induced hyperpolarization and consequently limits the dynamic range of this response. Our results provide insights into the role HCN1 channels play in retinal function as well as highlighting the need to consider retinal dysfunction in disease caused byHCN1variants. The characteristic changes in the electroretinogram open the possibility of using this tool as a biomarker for this HCN1 epilepsy variant and to facilitate development of treatments. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|