Figure 2.

Drug screening on the Q344X zebrafish identified carvedilol as a beneficial drug. (a) Carvedilol treatment on Q344X larvae resulted in a sustained scotopic light-off VMR (blue trace, N = 2 replicates of 24 larvae) compared to that of both DMSO-treated WT larvae and DMSO-treated Q344X larvae (black and red trace respectively, N = 9 replicates of 48 larvae in each group). Each trace shows the average displacement of each replicate, and the color ribbons indicate µ ± s.e.m. The two carvedilol replicates were highly consistent and not different from each other (High-Dimensional Nonparametric Multivariate Test, N = 24, T_HD = 1.78, p value = 0.91). Each replicate demonstrated a significant change in behavior for the duration of 30 s after light offset above DMSO-treated Q344X larvae (Hotelling’s T-squared test, N = 24, T = 378.0 and 456.0, df = 30, p value < 0.0001 for each replicate). (b) To determine if carvedilol’s effects are elicited through the retina, eyeless chokh fish were treated with carvedilol (blue trace) and their VMR was compared with untreated control (black trace). Carvedilol treatment did not increase the chokh VMR (Hotelling’s T-squared test, N = 24 larvae, T = 37.8, df = 30, p value = 0.946). (c) Q344X larvae were enucleated to determine if extraocular expression of Q344X RHO was causing the VMR seen with carvedilol treatment. Larvae were treated with carvedilol (blue trace) or DMSO (red trace) at 5 dpf and enucleated on the morning of 6 dpf. VMR was assessed at 7 dpf. Carvedilol showed no effect on enucleated Q344X larvae. (Hotelling’s T-squared test, N = 24 larvae, T = 28.8, df = 30, p value = 0.948). (d) Q344X larvae were treated with 100 μM adenylyl cyclase (ADCY) inhibitor SQ 22,536 (black trace) at 3 dpf to determine if inhibiting ADCY would improve the VMR compared to DMSO treatment (red trace). Treatment with SQ 22,563 significantly improve the Q344X VMR over DMSO treatment (Hotelling’s T-squared test, N = 3 replicates 24 larvae, T = 118, df = 30, p value < 0.0001).