Neurotoxicology of deltamethrin in the developing brain

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ABSTRACT Epidemiological studies identify early life exposure to pyrethroids as a threatening risk factor for attention- deficit hyperactivity disorder (ADHD). Because the reported risk of exposure is within no-observed-adverse- effect level (NOAEL) guidelines, environmental exposure to pyrethroids could be an underestimated leading cause of ADHD and other neurodevelopmental disorders in the general population. Animal models of early-life exposure to the pyrethroid pesticide deltamethrin (DM), a potent neurotoxin that acts on the insect voltage- gated Na+ (Nav) channel, recapitulates ADHD-like behavior through disruption of dopamine signaling in the nucleus accumbens (NAc), the brain region implicated in the human disease. Yet, the mechanism of toxicity of DM in the developing brain has not yet been determined. Recent studies from our group provide evidence for cross reactivity of DM with the mammalian Nav1.1 channel, an isoform expressed in fast-spiking parvalbumin (PV) inhibitory interneurons during development. These cells exert a powerful inhibitory control over the output of the NAc, which, if disrupted, leads to dopamine dysfunction with effects on locomotor activity, attention, and impulsivity, endophenotypes that characterize ADHD. In supporting studies conducted in an early-life DM exposure animal model we show regional accumulation of DM and loss in GABA in the NAc/striatum and demonstrate disruption of PV interneuron firing in the same brain region accompanied by ADHD-like behaviors. Building on this premise, we propose molecular (Aim 1), functional (Aim 2) and behavioral (Aim 3) studies to test the hypothesis that the primary mechanism of DM toxicity in the developing brain is to disrupt PV interneuron function leading to loss of local inhibitory control in the NAc and behavioral phenotypes common to ADHD. Outcomes of this study will provide new insights into the molecular-based understanding of risk factors for neurodevelopmental disorders providing guidance for therapeutic development against exposure.