Abstract
Purpose:
Phosphene perception is a characteristic side effect, occurring in patients treated with ivabradine. This drug is a selective bradycardic agent which reduces the heart rate by blocking HCN4-channels in the sinoatrial node. The induction of phosphenes by ivabradine is ascribed to the blockade of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in retinal photoreceptors. In the retina, HCN channels play an important role in efficient encoding of stimuli at high-frequency by shaping the photoreceptor membrane potential. Previous studies showed that blocking HCN channels by genetic knockout or pharmacology results in prolonged hyperpolarization of photoreceptor inner segments. Complementary to these studies, we here examined the effect of pharmacological HCN channel blockade on the encoding of visual signals by retinal ganglion cells (RGCs).
Methods:
We recorded spikes from individual ganglion cells of isolated mouse retina mounted on a multielectrode array. Responses to light stimuli as well as spontaneous spiking of ganglion cells were measured with and without administration of 3 µM ivabradine or 3 µM cilobradine, an alternative HCN channel blocker.
Results:
By analyzing the cells’ temporal filter properties, we found that administration of ivabradine or cilobradine prolonged the response delay and reduced responses to stimuli of high temporal frequencies, in agreement with previous studies of electroretinograms. Furthermore, we found that ON-type RGCs primarily showed increasing and OFF-type RGCs decreasing spontaneous spike rates during drug administration. OFF-type RGCs moreover changed their firing patterns to more burst-like spiking.
Conclusions:
Our data suggest that reduced band-pass filtering under pharmacological HCN-channel blockade underlies the measured imbalance of spontaneous activity between ON-type and OFF-type cells, which may contribute to the reported phosphene perception in treated patients.
Keywords: 531 ganglion cells •
641 perception •
503 drug toxicity/drug effects