Fig. 1

Fig. 1

GABA_AR PAMs enhance acoustic startle in zebrafish. Zebrafish were treated with the indicated compounds and analyzed for changes in behavioral responses. a The scatter plot quantifies acoustic startle response as a z-score (y-axis) in zebrafish treated with the indicated CNS-depressants (x-axis) at the indicated concentrations (colorbar). Each point represents the average of n = 12 wells and 6 experimental replicates (also listed in Supplementary Table 1). b These plots show how the indicated compounds impact zebrafish motor activity (y-axis) over time (x-axis) (n = 12 wells, shaded boundary = 95% confidence interval; nMI, normalized motion index). Colored bars above the x-axis represent the timing and duration of low-volume acoustic stimuli (gray bars) and violet light stimuli (purple bars). The vertical dotted line indicates where the first assay ends and the second begins. c Representative images of animals treated with the indicated compounds. Time stamps indicate the time elapsed from the initial presentation of a low-volume acoustic stimulus. d These plots compare the motor activity (y-axis) over time (x-axis) of animals treated with DMSO (gray) or etomidate (red) (n = 50 larvae). Consecutive stimuli (n = 60) are indicated by vertical gray bars. e Dose-response curve showing phenoscores at the indicated concentrations (each point represents n = 12 wells/dose, error bars: ± SD). f Bar plot showing normalized response to the indicated stimulus (tap or violet light) of animals treated with DMSO, 6 μΜ propofol, or 6 μΜ etomidate (n = 12 wells, error bars: ± SD) for the indicated durations. g Average phenoscores (y-axis) of zebrafish treated with the indicated compounds. Dashed lines intersecting the y-axis at 0.51 and 0.71 correspond respectively to 1% and 5% significance cutoffs, as determined from statistical simulations. Compounds are grouped by ligand class: (1) GABA_BR agonist, (2) GABA_AR orthosteric agonist, (3) PAM of δ-subunit containing GABA_ARs, (4) GABA_AR BZ-site PAM, (5) GABA_AR non-BZ-site PAM, (6) GABA_AR neurosteroid PAM, (7) GABA_AR anesthetic PAM