Novel electroretinographic assays to determine the function of retinal ganglion cells in normal and glaucomatous human and mouse retina

• Applicants: Privatdozent Dr. Cord Huchzermeyer; Dr. Anneka Joachimsthaler
• Subject Area: Ophthalmology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547108235

In the proposed project, we will determine the activity of retinal ganglion cells (RGCs) in the glaucomatous retina of human subjects and mice by using innovative stimuli in electroretinographic (ERG) recordings. Glaucoma leads to RGC degeneration and therefore to blindness. There is broad consensus that early diagnosis and therapy is essential, because lost RGCs cannot be replaced. Recent studies suggest early changes in the morphology of RGC dendrites to be reversible. State of the art methods that investigate retinal structure or function cannot detect these smaller changes in vivo. Aim of the proposed project is to implement new ERG protocols that reflect RGC activity and that enable a detection early stage glaucoma. We will use two novel stimuli for recording of RGC activity; i) sawtooth and ii) temporal white noise (TWN) stimulation. We will implement recording protocols, that can be used on both men and mice that can be implemented as functional endpoints both in clinical trials and that in clinical diagnostic routine. The sawtooth protocol can simulate a pattern ERGs (PERGs) by recording On- and Off-responses separately using rapid-on and a rapid-off sawtooth stimuli. Asymmetries between these two responses reflect non-linearities that probably originate in RGC activity. First results in glaucoma patients show significant changes in the sawtooth-ERG compared to control subjects. The proposed project aims at a further development of this method for the use in men and mice. The TWN stimulus is a randomized luminance modulation around a fixed mean luminance. The stimulus contains all temporal frequencies with equal amplitudes. This stimulus has characteristics that are more similar to natural scenes than conventional stimuli. The cross-correlation of the TWN stimulus with the ERG response results in the so-called impulse response function (IRF). Recent studies in humans, non-human primates and mice reveal a large and robust IRF component, that resembles on the one hand the RGC-driven PhNR in humans and non-human primates and on the other hand the RGC-driven STR in mice. We will investigate the hypothesis that this late component of the IRF reflects RGC activity and optimize the stimulation protocol to maximize the amplitude of this late component. The two stimulus protocols will be recorded in glaucoma patients and in a mouse model for glaucoma. We plan to perform a longitudinal study on glaucomatous mice to correlate the functional phenotype with the progression of the disease. Furthermore, we will perform structural (e.g. human: OCT; mouse: OCT, histology) and functional (human: PERG, perimetry, PhNR; mouse: STR, PhNR) examinations and correlate those with the results of sawtooth- and TWN-ERGs.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Jan Kremers