Early Synaptic Alterations and Selective Adhesion Signaling in Hippocampal Dendritic Zones Following Organophosphate Exposure.
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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 ?1 integrin, a component of adhesion receptors that regulate synapse maintenance and plasticity. The paraoxon-induced ?1 integrin response was targeted to synapses, and the two-fold increase in ?1 integrin was selective as other synaptic adhesion molecules were unchanged. Additionally, ?1 integrin-cofilin signaling was triggered by the exposure and correlations were found between the extent of synaptic decline and the level of ?1 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.
SUBMITTER: Farizatto KLG
PROVIDER: S-EPMC6484076 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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