Retinoschisin Deficiency Induces Persistent Aberrant Waves of Activity Affecting Neuroglial Signaling in the Retina
Cyril G. Eleftheriou, Carlo Corona, Shireen Khattak, Nazia M. Alam, Elena Ivanova, Paola Bianchimano, Yang Liu, Duo Sun, Rupesh Singh, Julia C. Batoki, Glen T. Prusky, J. Jason McAnany, Neal S. Peachey, Carmelo Romano, Botir T. Sagdullaev
Abstract
Genetic disorders that present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis, an early-onset inherited condition caused by mutations in the Rs1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of RS1-deficient male mice, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuroglial signals as early as postnatal day 15, when eyes normally open. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Mller glia, spanning all retinal layers and disrupting light-induced signaling. This study confers a role to RS1 beyond its function as an adhesion molecule, identifies an early onset for dysfunction in the course of disease, establishing a potential window for disease diagnosis and therapeutic intervention.