Pharmacological manipulation of oscillatory activity in the retina of the retinitis pigmentosa mouse model rd10 improves efficiency of electrical stimulation

• Die pharmakologische Manipulation der oszillatorischen Aktivität in der Retina des Retinitis Pigmentosa Mausmodells rd10 verbessert die Effizienz der elektrischen Stimulation

Gehlen, Jana; Müller, Frank (Thesis advisor); Spehr, Marc (Thesis advisor)

Aachen (2020)
Dissertation / PhD Thesis

Dissertation, RWTH Aachen University, 2020

Abstract

During the disease retinitis pigmentosa (RP), the photoreceptors degenerate over time, leading to blindness of the patient. The downstream retinal network including the output neurons - the ganglion cells (GCs) - persists. This provides the possibility to stimulate the retina electrically using retinal implants in order to elicit visual impressions. The rd10 mouse is a good model for human RP. Rd10 retina develops a pathological activity that can be recorded as oscillations in the local field potential and as bursts in GC spiking. This kind of activity is not observed in wildtype retina (WT). It was suggested, that this oscillatory activity reduces the efficiency of electrical stimulation by a retinal implant. The main part of this study deals with the analysis of the electrical activity in rd10 retina and in retinae of mice suffering from photoreceptor degeneration caused by mutations in the ClC-3 gene using multielectrode arrays (MEAs). In all animal models with degenerated retinae, I could observe oscillations at a frequency of 3-6 Hz. When using biphasic current pulses, the efficiency of stimulation - measured as ratio of spike rate after and before the stimulation pulse - was lower in the retina of rd10 and ClC channel-related degeneration models than in WT. The major hypothesis of this thesis states that oscillations interfere with electrical stimulation and predicts that, blocking oscillations should increase stimulation efficiency. By the use of inhibitory neurotransmitters and benzodiazepines like diazepam oscillatory activity could be blocked in all retinal degeneration models. Most importantly, at the same time the stimulation efficiency was strongly improved. It is worthwhile to continue with this approach, e.g. with application of other pharmacological agents. Stimulating the retina with pulse trains also led to an improvement of the stimulation efficiency. However, during repetitive stimulation, adaptation effects occurred which were not abolished during the treatment with diazepam. Possibilities to transfer the observed effects to human RP are discussed. This study may open the way to a therapy that supports electrical stimulation by retinal prostheses with pharmacological treatment.