Temporal Contrast Sensitivity Increases despite Photoreceptor Degeneration in a Mouse Model of Retinitis Pigmentosa

Abstract

The detection of temporal variations in amplitude of light intensity, or temporal contrast sensitivity (TCS), depends on the kinetics of rod photoresponse recovery. Uncharacteristically fast rod recovery kinetics are facets of both human patients and transgenic animal models with a P23H rhodopsin mutation, a prevalent cause of retinitis pigmentosa (RP). Here, we show that mice with this mutation (Rho P23H/+ ) exhibit an age-dependent and illumination-dependent enhancement in TCS compared with controls. At retinal illumination levels producing ≥1000 R*/rod/s or more, postnatal day 30 (P30) Rho P23H/+ mice exhibit a 1.2-fold to 2-fold increase in retinal and optomotor TCS relative to controls in response to flicker frequencies of 3, 6, and 12 Hz despite significant photoreceptor degeneration and loss of flash electroretinogram (ERG) b-wave amplitude. Surprisingly, the TCS of Rho P23H/+ mice further increases as degeneration advances. Enhanced TCS is also observed in a second model (rhodopsin heterozygous mice, Rho +/− ) with fast rod recovery kinetics and no apparent retinal degeneration. In both mouse models, enhanced TCS is explained quantitatively by a comprehensive model that includes photoresponse recovery kinetics, density and collecting area of degenerating rods. Measurement of TCS may be a non-invasive early diagnostic tool indicative of rod dysfunction in some forms of retinal degenerative disease.

Visual system hyperexcitability and compromised V1 receptive field properties in early-stage retinitis pigmentosa in mice

“…Similarly, the temporal-frequency threshold remained excellent in Rho P23H/WT mice, and was in fact elevated at 1-month of age (Figure 6G, H). These data correspond well with the ERG (improved kinetics, Figure 1 and Supplementary Figure 1; improved TCS by ERGs; (Pasquale et al, 2021)) and OMR findings in Rho P23H/WT mice (improved TCS by OMR) (Pasquale et al, 2021). Nevertheless, we also found detrimental changes for V1…”

“…Also, the contrast sensitivity in Rho P23H/WT mice remained at similar levels to those for WT mice, even at 3 months of age (Figure 6I, J). Altogether, the VEP and V1 single-unit recordings observed in young Rho P23H/WT mice reveal that hastened ERG kinetics (Figure 1D, H; Supplementary Figure 1F; (Pasquale et al, 2021)), maintained behavioral contrast and temporal frequency thresholds (Leinonen et al, 2020;Pasquale et al, 2021), and increased preference for lower SF stimuli (Figure 2A, C) are reflected in V1 function. We were unable to record meaningful responses to pattern stimuli in the most advanced disease state, in Rho P23H/P23H mice.…”

“…Pasquale et al . recently reported significantly improved temporal contrast sensitivity (TCS) in Rho P23H/WT mice (Pasquale et al ., 2021). The improvement arose from the rod-pathway, as the phenomenon remained when Rho P23H/WT mice were crossed with GNAT2 cpfl3/cpfl3 mice that lack cone function.…”

“…Rho P23H/WT mice (Pasquale et al, 2021). The improvement arose from the rod-pathway, as the phenomenon remained when Rho P23H/WT mice were crossed with GNAT2 cpfl3/cpfl3 mice that lack cone function.…”

Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model

“…In response to photoreceptor degeneration in RP, rod bipolar and horizontal cells are deafferented and, as a consequence, retract their dendrites [9]. Despite this degradative remodeling, rod bipolar cells [14] and rod photoreceptor cells [37,38] show increased sensitivity. We also observed dendrite truncation in our Pde6b STOP/STOP RP mouse model (Figs.…”