Influence of retinal states on the development and maintenance of retinofugal projections

Vision provides a critical interface with the physical world. This work examines visual development and vision loss in mice to glean the influence of the retinal state on visual connections. I first assessed the impact of retinal activity on the eye-specific segregation of retinal afferents in the lateral geniculate nucleus (LGN) of young Gβ5 -/- mice. Gβ5 is the fifth member of the β subfamily of heterotrimeric G proteins. Gβ5 binds and stabilizes the R7 family of regulators of G-protein signaling (RGS), which accelerate Gi/o GTP hydrolysis. Gβ5 -/- mice, which lack R7RGS activity, have malformed synapses in the outer plexiform layer (OPL) and impaired OPL transmission. Altered spontaneous retinal activity in Gβ5-/- mice at P7, P12, P14, and P28 correlates with impaired eye-specific segregation of retinal afferents in the LGN at corresponding timepoints. However, Gβ5-/- mice exhibit a normal transition from cholinergic to glutamatergic drive that corresponds with a temporary recovery of refinement at P10. Thus the abnormal-normal-abnormal pattern of activity in the retina is coupled with abnormal-normal-abnormal segregation. This activity-segregation profile suggests activity may instruct early retinogeniculate development. nob mice, which also exhibit impaired OPL transmission, have aberrant retinal waves that align with loss of segregation. nobxGβ5-/- mice have similar levels of segregation as Gβ5-/- at P21, but activity only similar P14 nobxGβ5-/- and Gβ5-/- RGCs. This suggests that the critical period of eye-specific segregation closes shortly after P14 and that R7RGS activity is critically important to postnatal RGCs. Next, I investigated the aged visual system via the retinofugal projections of mice with retinal remodeling after photoreceptor degeneration (PD). ΔCT mice, with mild remodeling, and TG9N mice, with aggressive remodeling, retain gross anatomical and physiological connectivity in the presence of attenuated visual activity compounded by organic remodeling. However, the magnitude of pupillary light responses in PD mice was diminished. Reduced melanopsin signal in the retina, not downstream anomalies, explains this functional deficiency. These observations suggest that changes to eye-specific segregation are limited once projections are established, regardless of retinal activity or remodeling. These observations bode well for future retina-based treatments of vision loss