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

Abstract

Purpose : X-linked juvenile retinoschisis (XLRS) is an early onset inherited condition characterized by abnormal retinoschisin (RS1) expression, early visual deficiencies and cystic retinal lesions. We characterize a series of novel dysfunctions at the cellular level of the developing retina of mice lacking RS1.

Methods : We studied spontaneous intracellular calcium dynamics in male mice expressing GCaMP6f in neuronal, glial, and vascular cells and compared results from Rs1 knockouts (Rs1^-/Y) and controls (Rs1^+/Y). Optophysiological assessment was carried out in live wholemount retinal explants of cohorts aged P10-11, P14-15, P20-22, and P60-65. Additionally, we performed in vivo OCT imaging of retinal cysts and immunohistochemical characterization of retinoschisin expression in the retina.

Results : The development of retinal cysts imaged in vivo by OCT is paralleled by the appearance of aberrant spontaneous neuro-glial signals after postnatal day 13. These presented as glutamate-driven wavelets of neuronal and Müller glia activity spanning all retinal layers that disrupt light-induced signaling.

Conclusions : This study highlights the critical role that RS1 plays in early retinal development. Additionally, it confers a functional role to RS1 beyond the scope of an adhesion molecule and identifies a tight bracket for the onset of dysfunction, a potential temporal target for therapeutic intervention.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.