Anticholinesterases induce multigenic transcriptional feedback response suppressing cholinergic neurotransmission

Cholinesterase inhibitors (anti-ChEs) include a wide range of therapeutic, agricultural and warfare agents all aimed to inhibit the catalytic activity of the acetylcholine (ACh) hydrolysing enzyme acetylcholinesterase (AChE). In addition to promoting immediate excitation of cholinergic neurotransmis sion through transient elevation of synaptic ACh levels, anti-ChEs exposure is associated with long-term effects reminiscent of post-traumatic stress disorder. This suggested that exposure to anti-ChEs leads to persistent cha nges in brain proteins and called for exploring the mechanism(s) through wh ich such changes could occur. For this purpose, we established an in vitro system of perfused, sagittal mouse brain slices which sustains authentic tr anscriptional responses for over 10 h and enables the study of gene regulat ion under controlled exposure to anti-ChEs. Slices were exposed to either o rganophosphate or cabamate anti-ChEs, both of which induced within 10 min e xcessive overexpression of the mRNA. encoding the immediate early response transcription factor c-Fos. Twenty minutes later we noted 8-fold increases over control levels in AChE mRNA, accompanied by a 3-fold decrease in the m RNAs encoding for the ACh synthesizing enzyme choline acetyltranferase (ChA T) and the vesicular ACh transporter (VAChT). No changes were detected in s ynaptophysin mRNA levels. These modulations in gene expression paralleled t hose taking place under in vivo exposure. Of particular concern is the poss ibility that feedback processes leading to elevated levels of brain AChE ma y be similarly associated with low-level exposure to common organophosphoro us anti-cholinesterases, and lead to long-term deleterious changes in cogni tive functions. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.