Abstract
Organophosphates account for many of the world’s deadliest poisons. They inhibit acetylcholinesterase causing cholinergic crises that lead to seizures and death, while survivors commonly experience long-term neurological problems. Here, we treated brain explants with the organophosphate compound paraoxon and uncovered a unique mechanism of neurotoxicity. Paraoxon-exposed hippocampal slice cultures exhibited progressive declines in synaptophysin, synapsin II, and PSD-95, whereas reduction in GluR1 was slower and NeuN and Nissl staining showed no indications of neuronal damage. The distinctive synaptotoxicity was observed in dendritic zones of CA1 and dentate gyrus. Interestingly, declines in synapsin II dendritic labeling correlated with increased staining for β1 integrin, a component of adhesion receptors that regulate synapse maintenance and plasticity. The paraoxon-induced β1 integrin response was targeted to synapses, and the two-fold increase in β1 integrin was selective as other synaptic adhesion molecules were unchanged. Additionally, β1 integrin–cofilin signaling was triggered by the exposure and correlations were found between the extent of synaptic decline and the level of β1 integrin responses. These findings identified organophosphate-mediated early and lasting synaptotoxicity which can explain delayed neurological dysfunction later in life. They also suggest that the interplay between synaptotoxic events and compensatory adhesion responses influences neuronal fate in exposed individuals.
Highlights
The organophosphate toxin paraoxon (Pxn) is the main active metabolite of the pesticide parathion used in the United States and other countries, in which parathion is converted to Pxn by oxidation in the soil and the liver[16,17]
Pxn was studied in hippocampal slice cultures to understand organophosphate-mediated effects that may underlie the long-term symptoms in survivors of nerve agent exposure
Cultured hippocampal slices have been widely used to study the actions of neurotoxins because they provide a stable tissue model that maintains the native organization and circuitry of the adult hippocampus and exhibits the pathogenic responsiveness found in vivo[13,26,27,28,29,30,31,32]
Summary
The organophosphate toxin paraoxon (Pxn) is the main active metabolite of the pesticide parathion used in the United States and other countries, in which parathion is converted to Pxn by oxidation in the soil and the liver[16,17]. Pxn causes excitotoxic brain damage through the irreversible inhibition of acetylcholinesterase[18], affecting behavior, cognition, and may trigger seizures and elongate epileptiform activity[19,20,21,22]. The Pxn toxin and related organophosphates cause similar neurological problems, often long after an exposure[9,21,22,23]. Pxn disrupts developmental processes underlying synaptic connectivity and cognitive ability in children, who appear to be vulnerable to anticholinesterase effects[24,25]. Pxn was studied in hippocampal slice cultures to understand organophosphate-mediated effects that may underlie the long-term symptoms in survivors of nerve agent exposure. Pxn was infused into mature slice cultures in order to examine the pathogenic cascade associated with anticholinesterase toxicity and its effect on the profile of synaptic constituents
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