OPIDN and SWS overexpression flies still have 50% of the phospholipase/esterase activity found in wild type after TOCP treatment. If OPIDN results solely from reduced phospholipase activity, SWS overexpression and the resulting increase in activity should prevent or at least reduce the toxic Epimedoside-A effects after TOCP exposure. Furthermore, reducing the levels of SWS by treating heterozygous sws1 flies did not increase the toxicity, but protected the flies form behavioral deficits and neurodegeneration. That sws1 heterozygous flies were protected from the delayed symptoms caused by TOCP and SWS overexpressing flies were more sensitive, at least when analyzing the degeneration, strongly suggested that the delayed phenotypes are caused by another function of SWS, than the phospholipase function. It also supported the hypothesis that these defects are caused by inducing a toxic gain-of function which is prevented when the amount of the toxic, TOCP-modified SWS is reduced, as in the case of sws1 heterozygous flies. Surprisingly, changes in SWS levels had no effect on the TOCP-induced neurite shortening in primary neuronal cultures, suggesting that this acute phenotype is due to a different toxic mechanism of TOCP. Indeed, treatment with paraoxon, a potent AChE inhibitor that does not induce OPIDN resulted in a very similar neurite retraction, further supporting our assumption that mechanisms of the acute toxicity are different or might even not be mediated by NTE. We previously described that SWS can act as a non-canonical regulatory subunit of protein kinase A by binding and inhibiting the C3 catalytic subunit. We therefore tested whether the gain-of function effect of TOCP on SWS could be due to altering the interaction of SWS with PKA-C3. Indeed, exposing flies to TOCP resulted in a significant decrease in PKA activity, a result that was confirmed for vertebrate NTE using rat primary neurons. Like SWS, rodent NTE did bind to the C3 subunit whereas it did not interact with the other two catalytic subunits of assumption that mechanisms of the acute toxicity are different or might even not be mediated by NTE. We previously described that SWS can act as a non-canonical regulatory subunit of protein kinase A by binding and inhibiting the C3 catalytic subunit. We therefore tested whether the gain-of function effect of TOCP on SWS could be due to altering the interaction of SWS with PKA-C3. Indeed, exposing flies to TOCP resulted in a significant decrease in PKA activity, a result that was confirmed for vertebrate NTE using rat primary neurons. Like SWS, rodent NTE did bind to the C3 subunit whereas it did not interact with the other two catalytic subunits of flies, suggesting that the PKA-regulatory function is conserved in vertebrate proteins. In this context, it is noteworthy to mention that vertebrates have a C3 orthologous catalytic subunit, called Pkare in mouse and PrKX in humans, and that these subunits are more conserved between the different species than they are related to different subtypes from one species. As observed in flies, TOCP treatment of hippocampal neurons reduced PKA activity, suggesting that TOCP also interferes with the release and activation of the vertebrate catalytic subunits from NTE. To Salvianolic-acid-B obtain further support for our model that reduced PKA activity plays a role in the delayed symptoms of OPIDN, we used flies that expressed additional PKA-C3 and indeed this protected them from TOCP-induced behavioral and degenerative defects.