Domoic acid disruption of neurodevelopment and behaviorinvolves altered myelination in the spinal cord

Harmful algal blooms (HABs) produce potent neurotoxins that threaten human health. Early life exposure to low levels of the HAB toxin domoic acid (DomA) produces long-lasting behavioral deficits, but the mechanisms involved are unknown. Using zebrafish, we investigated the developmental window of susceptibility to low doses of DomA and examined cellular and molecular targets. Larvae exposed to DomA at 2 days post-fertilization (dpf), but not at 1 or 4 dpf, showed consistent deficits in startle behavior including reduced responsiveness and altered kinematics. Similarly, myelination in the spinal cord was disorganized after exposure only at 2 dpf. Time-lapse imaging revealed disruption of the initial stages of myelination. DomA down-regulated genes required for maintaining myelin structure and the axonal cytoskeleton. These results identify a developmental window of susceptibility to DomA-induced behavioral deficits involving altered gene expression and disrupted myelin structure, and establish a zebrafish model for investigating the underlying mechanisms. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=34 SRC="FIGDIR/small/842294v1_ufig1.gif" ALT="Figure 1"> View larger version (8K): org.highwire.dtl.DTLVardef@198491org.highwire.dtl.DTLVardef@14e6e84org.highwire.dtl.DTLVardef@39d118org.highwire.dtl.DTLVardef@1cea6c7_HPS_FORMAT_FIGEXP M_FIG C_FIG