Reduced synaptic vesicle density and aberrant synaptic localization caused by a splice site mutation in the Rs1h gene

X-linked retinoschisis (XLRS) is a common form of inherited macular degeneration caused by mutations in the RS1 gene. Whereas the role of RS1 has been implicated in the synaptic structure as well as layer organization in the retina, the pathological effect of a defective RS1 gene on the synaptic interaction between photoreceptor cells and second-order neurons has not been thoroughly investigated. In this study, we perform a detailed characterization of the retinal synaptic phenotypes caused by a splice site mutation in the murine RS1 homolog (Rs1h(tmgc1)). Electron microscopic analysis showed that presynaptic terminals of photoreceptor cells contain a lower areal density of synaptic vesicles in the Rs1h(tmgc1) retina. Examination of the synaptic interactions in the outer plexiform layer also revealed ectopic localization of photoreceptor cell presynaptic markers and elongation of neurites from postsynaptic neurons (bipolar and horizontal cells), which are observed in other mouse models with defective photoreceptor cell molecules. Consistent with these synaptic abnormalities, ERG analysis of young Rs1h(tmgc1) mice revealed attenuation of the b-wave with preservation of the a-wave. These results demonstrate that RS1H has functional significance in the morphology and function of the synapse between photoreceptors and second-order neurons. A developmental study from postnatal day (P) 15 through P19 showed that synaptic interactions form normally, and structural abnormalities occur after completion of synaptic formation suggesting that RS1H is important for the maintenance of this synaptic interaction. Thus, Rs1h(tmgc1) mice may serve as a new genetic model for human XLRS and other synaptic disorders.