Differential Effects of HCN Channel Block on On and Off Pathways in the Retina as a Potential Cause for Medication-Induced Phosphene Perception

Bemme, Sebastian; Weick, Michael; Gollisch, Tim

doi:10.1167/iovs.17-21572

Cited by 11 publications

(17 citation statements)

References 69 publications

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“…The observed ON/OFF imbalance may account for the visual symptoms commonly associated with abrupt changes in light intensity seen in ivabradine treated patients (Borer et al, 2003;Cervetto et al, 2007). Similar suggestion was made by Bemme et al (2017), who demonstrated that ivabradine differentially affects the activity of the ON and OFF ganglion cells in mouse retina. The ON cells showed reduced response gain, whereas OFF cells experienced an increase in response threshold under temporal white noise stimulation.…”

Section: Discussionmentioning

confidence: 56%

“…We chose concentration of 75 μM ZD7288, because it had saturating effect for both the b-and d-wave amplitude changes. Ivabradine was used in a concentration of 30 μM on the basis of our preliminary experiments, where concentrations of 3, 30 and 60 μM were tested in accordance with other retinal studies: 3 μM (Della Santina et al, 2012;Bemme et al, 2017), 30 μM (Demontis et al, 2009).…”

Section: Subjects and Drug Applicationmentioning

confidence: 99%

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Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs

Popova¹,

Kupenova²

2020

Acta Neurobiologiae Experimentalis

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Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are well expressed in the vertebrate retina. Their role in formation of electroretinographic (ERG) responses to stimulus onset (b-wave) and stimulus offset (d-wave) are largely unknown. In this study we investigated the effects of pharmacological blockade of HCN channels (with ZD7288 or ivabradine) on the ERG band d-waves in dark adapted frog eyecup preparations. Initially, the dose-response relationship of ZD7288 effects on the band d-waves was investigated. Afterwards, the effects of 75 μM ZD7288 on the stimulus-response function of the ERG band d-waves were explored over a wide intensity range (10 log units). Finally, the effects of 30 μM ivabradine on the same function were studied. Perfusion with 75 μM ZD7288 did not change the absolute and relative sensitivity of the ERG ON and OFF responses. It caused an enhancement of the d-wave amplitude at all suprathreshold stimulus intensities, while the b-wave amplitude was slightly enhanced only in the range of higher intensities. As a result of the greater blocker effect on the OFF response amplitude, the b/d amplitude ratio was significantly decreased over the whole intensity range. ZD7288 caused a prolongation of the b-wave half-width duration, but a shortening of the d-wave half-width duration at higher intensities. Similar results were obtained when 30 μM ivabradine was used for HCN channel blockade. Our results clearly demonstrate that the blockade of retinal HCN channels changes the balance between the ON and OFF responses in the distal frog retina. This ON/OFF imbalance may be one of the causes for visual disturbances reported in ivabradine treated patients.

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Section: Discussionmentioning

confidence: 56%

Section: Subjects and Drug Applicationmentioning

confidence: 99%

Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs

Popova¹,

Kupenova²

2020

Acta Neurobiologiae Experimentalis

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“…HCN currents are critical for rhythmic activities in the heart pacemaker cells and neurons in the central nervous system (Baker et al, 1997 ; Day et al, 2005 ; Knop et al, 2008 ). In contrast, in the retina HCN channels have been associated with transient signaling as well as higher-frequency tuning (Cangiano et al, 2007 ; Della Santina et al, 2012 ; Puthussery et al, 2013 ; Bemme et al, 2017 ). These results suggest that HCN currents shape the high-frequency responses.…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic Modulation of Signal Processing in a Subset of Retinal Bipolar Cells

Hellmer

Bohl

Hall

et al. 2020

Front. Cell. Neurosci.

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The retina and the olfactory bulb are the gateways to the visual and olfactory systems, respectively, similarly using neural networks to initiate sensory signal processing. Sensory receptors receive signals that are transmitted to neural networks before projecting to primary cortices. These networks filter sensory signals based on their unique features and adjust their sensitivities by gain control systems. Interestingly, dopamine modulates sensory signal transduction in both systems. In the retina, dopamine adjusts the retinal network for daylight conditions ("light adaptation"). In the olfactory system, dopamine mediates lateral inhibition between the glomeruli, resulting in odorant signal decorrelation and discrimination. While dopamine is essential for signal discrimination in the olfactory system, it is not understood whether dopamine has similar roles in visual signal processing in the retina. To elucidate dopaminergic effects on visual processing, we conducted patch-clamp recording from second-order retinal bipolar cells, which exhibit multiple types that can convey different temporal features of light. We recorded excitatory postsynaptic potentials (EPSPs) evoked by various frequencies of sinusoidal light in the absence and presence of a dopamine receptor 1 (D 1 R) agonist or antagonist. Application of a D 1 R agonist, SKF-38393, shifted the peak temporal responses toward higher frequencies in a subset of bipolar cells. In contrast, a D 1 R antagonist, SCH-23390, reversed the effects of SKF on these types of bipolar cells. To examine the mechanism of dopaminergic modulation, we recorded voltage-gated currents, hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels, and low-voltage activated (LVA) Ca 2+ channels. SKF modulated HCN and LVA currents, suggesting that these channels are the target of D 1 R signaling to modulate visual signaling in these bipolar cells. Taken together, we found that dopamine modulates the temporal tuning of a subset of retinal bipolar cells. Consequently, we determined that dopamine plays a role in visual signal processing, which is similar to its role in signal decorrelation in the olfactory bulb.

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“…Neben Messungen von Elektroretinogrammen (ERGs) an lebenden Versuchstieren (Della Santina et al 2010) konnte ein ähnliches Ergebnis auch an Knock-Out-Modellen mit gentechnisch "ausgeschalteten" HCN1-und HCN2-Kanälen erhoben werden (Della Santina et al 2012;Knop et al 2008;Seeliger et al 2011). Kürzlich wurden zudem Auswirkungen einer HCN-Kanal-Inhibition auf die Ganglienzellen nachgewiesen, deren Aktivität und Antwortreaktion auf Lichtreize durch Ivabradin verändert wurden (Bemme et al 2017). Diese Befunde untermauern die Bedeutung des Ih-Ionenstroms für die Informationsverarbeitung in der Netzhaut und lassen einen Zusammenhang zu den visuellen Nebenwirkungen bei medikamentöser Anwendung von Ivabradin erkennen.…”

Section: Abkürzungsverzeichnisunclassified

“…In einer aktuell veröffentlichten Studie wurde der Effekt von Ivabradin auf die Ganglienzellsignale untersucht, deren Antwortverhalten sich durch die HCN-Kanalblockade veränderte (Bemme et al 2017). Bei den ON-Ganglienzellen nahm die Spontanaktivität zu, während die Spontanaktivität der OFF-Ganglienzellen sich insgesamt reduzierte und salvenartig auftrat.…”

Section: Hcn-kanäle In Der Retina Und Ihr Einfluss Auf Die Zellsignaleunclassified

Einfluss des HCN-Kanalblockers Ivabradin auf die Kontrastsensitivität und zeitliche Auflösung der Signalverarbeitung in der Retina

Lauterbach¹

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Differential Effects of HCN Channel Block on On and Off Pathways in the Retina as a Potential Cause for Medication-Induced Phosphene Perception

Abstract: Our data suggest that pharmacologic HCN channel block in the retina leads to a shift in the relative activity of the On and Off pathways of the retina. We hypothesize that this imbalance may underlie the medication-induced perception of phosphenes.

Cited by 11 publications

References 69 publications

Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs

Effects of HCN channel blockade on the intensity-response function of electroretinographic ON and OFF responses in dark adapted frogs

Dopaminergic Modulation of Signal Processing in a Subset of Retinal Bipolar Cells

Einfluss des HCN-Kanalblockers Ivabradin auf die Kontrastsensitivität und zeitliche Auflösung der Signalverarbeitung in der Retina

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