Differential Behavioral Responses of cntnap2ab Mutants to Psychoactive Agents
(A) The 14 psychoactive drugs tested in cntnap2aΔ121/Δ121cntnap2bΔ31i/Δ31i and wild-type larvae, their biological targets, and the rationale for their selection. The following classes of drugs are shown: correlating (blue), anti-correlating (purple), drugs interacting with the GABA-A receptor (orange), and risperidone (green).
(B and C) Dose-response effects of the NMDA receptor antagonist, (-)-MK-801, on night waking activity at 5 dpf (B) and the non-benzodiazepine GABA-A receptor agonist zolpidem on average night waking activity at 4–6 dpf (C) in wild-type (WT; blue) and cntnap2ab (red) larvae (p = 0.002, (-)-MK-801; p = 0.0003, zolpidem; two-way ANOVA, genotype × drug interaction).
(D and E) Significant enrichment of NMDA receptor antagonists (D) and GABA receptor antagonists (E) in the top ranks of correlating drugs (p = 0.031, NMDA-R antagonists; p = 0.034, GABA-R antagonists; Kolmogorov-Smirnov test).
(F) Hierarchical clustering of the behavioral profiles of wild-type or cntnap2b larvae exposed to 14 psychoactive agents at three doses each. Each rectangle in the clustergram represents the Z score relative to the behavior of wild-type or mutant larvae exposed to DMSO alone (magenta, higher than DMSO; cyan, lower than DMSO).
(G) Magnified sections highlight the behavioral fingerprints of wild-type and cntnap2ab larvae in response to zolpidem (20 μM).
(H) Pairwise Euclidean distances between wild-type and cntnap2b responses to psychoactive agents in the PCA. Note that zolpidem and (±)-baclofen produce the strongest differential responses.
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