Plasticity in rescued retina – capacity and mechanisms

• Applicant: Professorin Dr. Susanne Koch
• Subject Area: Ophthalmology ; Anatomy and Physiology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 393313446

The most common cause of inherited blindness is retinitis pigmentosa (RP), a retinal degenerative disease, driven by mutations in the light-sensitive rod photoreceptor cells. While the most profound feature of RP pathology is progressive photoreceptor loss, the retina undergoes other changes. In the photoreceptors, themselves, the outer segment (OS), a specialized membrane-rich light-receptive organelle gradually shortens until it is lost entirely – just before photoreceptors die. The neural circuitry is also altered – with abnormal synaptic communication between mutant rods and their postsynaptic partners (horizontal and bipolar cells), and hyperactive circuits – including increased and rhythmic spiking in retinal ganglion cells (RGCs). RP patients are diagnosed after disease onset and, thus, during ongoing degeneration and retinal remodeling. Using RP mouse models, I have demonstrated that the most promising treatment for RP, gene therapy, halts photoreceptor death, even at very advanced disease stages. I have also shown that gene therapy halts any further OS shortening, although post-rescue OSs are maintained at lengths that are shorter than wild-type, and they are also dysmorphic. In addition, I demonstrated that some rescued (wild-type) rods migrate into areas vacated by untreated, dying rods.In this proposal, we test the hypothesis that neuronal circuits in rescued RP retina undergo remodeling and partial restoration that is driven by divergent mechanisms. We will do this by first determining the extent to which rescued rods reform normal synaptic connections at different phases of disease progression (Aim 1). Secondly, we will determine whether rescued rods that relocate to untreated zones form functional circuits, and whether the movement and/or reintegration are driven by rod death and/or aberrant RGC activity (Aim 2); indeed, in normal developing retina, spontaneous activity of RGCs regulates cell migration and synaptic refinement. Lastly, we will investigate whether persistent dysregulation of microRNAs (miRNAs, short noncoding nucleotides regulating expression of target genes) may, in part, underlie the persistence of the post-rescue dysmorphic OS phenotype post-rescue (Aim 3); in normal retinas, miRNA dysregulation has been linked to OS shortening. The significance of these studies is that they provide a critical knowledge base for designing vision rescue strategies.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: ERG ; Multielektrodenarray-System
• Instrumentation Group: 3440 Elektrophysiologische Meßsysteme (außer 300-309 und 340-343) ; 3690 Sonstige Geräte für fachärztlichen Gebrauch