Retinoschisin deficiency induces persistent aberrant waves of activity affecting neuroglial signaling in the retina

Genetic disorders which 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 (XLRS), 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 mice lacking RS1, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 13. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Muller glia, spanning all retinal layers and disrupting light-induced signaling. This study highlights a critical role for RS1 in early retinal development with a potential to disrupt circuit formation to central targets. Additionally, it confers a functional role to RS1 beyond the scope of an adhesion molecule and identifies an early onset for dysfunction, a potential temporal target for therapeutic intervention and diagnosis. Significance Statement/ HighlightsO_LIPhotoreceptor inner segments express Rs1 at P5, after which RS1 protein is detected in the inner segments by P9 and throughout the retina at later ages, with structural abnormalities observed by optical coherence tomography at P13 in Rs1 mutant mouse models. C_LIO_LIAberrant glutamate-driven wavelets identified by GCaMP6f-based analyses are a novel pathophysiological feature of RS1 deficient mice that emerge after maximal RS1 expression. C_LIO_LIMuller glia display abnormal radial glutamate-driven coordinated and sporadic bursts of activity in RS1-deficient mice. C_LIO_LIThese data identify a novel pathophysiological feature of RS1-deficient mice and define a window where treatments might be most effective. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/457777v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@3f27eborg.highwire.dtl.DTLVardef@55e5a4org.highwire.dtl.DTLVardef@1577435org.highwire.dtl.DTLVardef@8e55b3_HPS_FORMAT_FIGEXP M_FIG C_FIG