Acetylcholinesterase as a window onto stress responses

It has long been known that cholinergic neurotransmission is intimately associated with mammalian stress responses. Inhibition of acetylcholinesterase (AChE), like stress, elevates the levels of acetylcholine (ACh) in the short term, and both conditions induce some common long-lasting behavioral symptoms. Therefore, AChE manipulations provide an interesting window onto stress responses. Like many other stimuli, both stress and inhibition of AChE cause an increase in AChE gene expression that is also associated with a shift in its pre-mRNA splicing pattern. Of the several variants of AChE that arise due to alternative splicing, it is specifically the usually rare, soluble AChE-R variant that is up-regulated. Transgenic mice that over-express AChE also show many of the same symptoms as stress: erratic behavior following circadian light/dark shift, progressive failure of learning and memory, intensified long-term potentiation (LTP), development of neuropathologies, progressive muscle fatigue and degeneration of neuromuscular junctions. Altered expression of other cholinergic proteins in these mice, e.g. protein kinase CβII choline acetyltransferase and the high affinity choline transporter, suggests chronic feedback responses to the cholinergic imbalance. Stress-associated characteristics can be ameliorated in mice and humans by treatment with antisense agents that induce selective destruction of AChE-R, which provides further support for changes in alternative splicing, and in particular the accumulation of this variant, having a role in the etiology of stress responses.