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Acute stress facilitates long-lasting changes in cholinergic gene expression

Nature volume 393, pages 373–377 (1998)Cite this article

A Corrigendum to this article was published on 25 November 2015

Abstract

Acute traumatic stress may lead to post-traumatic stress disorder (PTSD)1, which is characterized by delayed neuropsychiatric symptoms including depression, irritability, and impaired cognitive performance2. Curiously, inhibitors of the acetylcholine-hydrolysing enzyme acetylcholinesterase may induce psychopathologies that are reminiscent of PTSD3,4. It is unknown how a single stressful event mediates long-term neuronal plasticity. Moreover, no mechanism has been proposed to explain the convergent neuropsychological outcomes of stress and of acetylcholinesterase inhibition. However, acute stress elicits a transient increase in the amounts released of the neurotransmitter acetylcholine and a phase of enhanced neuronal excitability5. Inhibitors of acetylcholinesterase also promote enhanced electrical brain activity6, presumably by increasing the survival of acetylcholine at the synapse. Here we report that there is similar bidirectional modulation of genes that regulate acetylcholine availability after stress and blockade of acetylcholinesterase. These calcium-dependent changes in gene expression coincide with phases of rapid enhancement and delayed depression of neuronal excitability. Both of these phases are mediated by muscarinic acetylcholine receptors. Our results suggest a model in which robust cholinergic stimulation triggers rapid induction of the gene encoding the transcription factor c-Fos. This protein then mediates selective regulatory effects on the long-lasting activities of genes involved in acetylcholine metabolism.

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Figure 1: Acute stress and anticholinesterases modulate CNS gene expression similarly.
Figure 2: Delayed suppression of the hyperexcitation evoked by AChE inhibition.
Figure 3: Physiological and transcriptional responses both depend on intracellular Ca2+ accumulation and Na+ influx.
Figure 4: Long-term changes in AChE activity following stress.
Figure 5: Selective induction of read-through AChE mRNA following stress and AChE inhibition.

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References

  1. Sapolsky, R. M. Why stress is bad for your brain. Science 273, 749–750 (1996).

    Article  ADS  CAS  Google Scholar 

  2. Gurvits, T. V. et al. Neurological status of Vietnam veterans with chronic posttraumatic stress disorder. J. Neuropsych. Clin. Neurosci. 5, 183–188 (1993).

    Article  CAS  Google Scholar 

  3. Rosenstock, L., Keifer, M., Daniell, W. E., McConnell, R. & Claypoole, K. Chronic central nervous system effects of acute organophosphate pesticide intoxication. Lancet 338, 223–227 (1991).

    Article  CAS  Google Scholar 

  4. Wickelgr, I. The big easy serves up a feast to visiting neuroscientists: rat model for Gulf War Syndrome? Science 278, 1404 (1998).

    Article  ADS  Google Scholar 

  5. Imperato, A., Puglisi-Allegra, S., Casolini, P. & Angellucci, L. Changes in brain dopamine and acetylcholine release during and following stress are independent of the pituitary-adrenocortical axis. Brain Res. 538, 111–117 (1991).

    Article  CAS  Google Scholar 

  6. Ennis, M. & Shipley, M. T. Tonic activation of locus coeruleus neurons by systemic or intracoerulear microinjection of an irreversible acetylcholinesterase inhibitor: increased discharge rate and induction of c-fos. Exp. Neurol. 118, 164–177 (1992).

    Article  CAS  Google Scholar 

  7. Friedman, A. et al. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Med. 2, 1382–1385 (1996).

    Article  CAS  Google Scholar 

  8. Ben Aziz-Aloya, R. et al. Expression of a human acetylcholinesterase promoter-reporter construct in developing neuromuscular junctions of Xenopus embryos. Proc. Natl Acad. Sci. USA 90, 2471–2475 (1993).

    Article  ADS  CAS  Google Scholar 

  9. Li, Y., Camp, S., Rachinsky, T. L., Bongiorno, C. & Taylor, P. Promoter elements and transcriptional control of the mouse acetylcholinesterase gene. J. Biol. Chem. 268, 3563–3572 (1993).

    CAS  Google Scholar 

  10. Bausero, P. et al. Identification and analysis of the human choline acetyltransferase gene promoter. Neuroreport 4, 287–290 (1993).

    Article  CAS  Google Scholar 

  11. Cervini, R. et al. Specific vesicular acetylcholine transporter promoters lie within the first intron of the rat choline acetyltransferase gene. J. Biol. Chem. 270, 2465–2467 (1995).

    Article  Google Scholar 

  12. Cole, A. E. & Nicoll, R. A. Acetylcholine mediates a slow synaptic potential in hippocampal pyramidal cells. Science 221, 1299–1301 (1983).

    Article  ADS  CAS  Google Scholar 

  13. Ghosh, A., Ginty, D. D., Bading, H. & Greenberg, M. E. Calcium regulation of gene expression in neuronal cells. J. Neurobiol. 25, 294–303 (1994).

    Article  CAS  Google Scholar 

  14. Seidman, S. et al. Synaptic and epidermal accumulations of human acetylcholinesterase is encoded by alternative 3′-terminal exons. Mol. Cell. Biol. 15, 2993–3002 (1995).

    Article  CAS  Google Scholar 

  15. Karpel, R. et al. Expression of three alternative acetylcholinesterase messenger RNAs in human tumor cell lines of different tissue origins. Exp. Cell Res. 210, 268–277 (1994).

    Article  CAS  Google Scholar 

  16. Layer, P. G. & Willbold, E. Novel functions of cholinesterases in development, physiology and disease. Prog. Histochem. Cytochem. 29, 1–99 (1995).

    CAS  Google Scholar 

  17. Koenigsberger, C., Chiappa, S. & Brimijoin, S. Neurite differentiation is modulated in neuroblastoma cells engineered for altered acetylcholinesterase expression. J. Neurochem. 69, 1389–1397 (1997).

    Article  CAS  Google Scholar 

  18. Sternfeld, M. et al. Acetylcholinesterase enhances neurite growth and synapse development through alternate contributions of its hydrolytic capacity, core protein and variable C-termini. J. Neurosci. 18, 1240–1249 (1998).

    Article  CAS  Google Scholar 

  19. Ichtchenko, K., Nguyen, T. & Sudhof, T. C. Structures, alternative splicing, and neurexin binding of multiple neuroligins. J. Biol. Chem. 271, 2676–2682 (1996).

    Article  CAS  Google Scholar 

  20. Beeri, R. et al. Transgenic expression of human acetylcholinesterase induces progressive cognitive deterioration in mice. Curr. Biol. 5, 1063–1071 (1995).

    Article  CAS  Google Scholar 

  21. 1. Andres, C. et al. ACHE transgenic mice display embryonic modulations in spinal cord CHAT and neurexin Iβ gene expression followed by late-onset neuromotor deterioration. Proc. Natl Acad. Sci. USA 94, 8173–8178 (1997).

    Article  ADS  CAS  Google Scholar 

  22. Beeri, R. et al. Enhanced hemicholinium binding and attenuated dendrite branching in cognitively impaired ACHE-transgenic mice. J. Neurochem. 69, 2441–2451 (1997).

    Article  CAS  Google Scholar 

  23. Knapp, M. J. et al. A30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. J. Am. Med. Assoc. 271, 985–991 (1994).

    Article  CAS  Google Scholar 

  24. Winker, M. A. Tacrine for Alzheimer's disease: which patient, what dose? J. Am. Med. Assoc. 271, 1023–1024 (1994).

    Article  CAS  Google Scholar 

  25. Sharabi, Y. et al. Survey of symptoms following intake of pyridostigmine during the Persian gulf war. Isr. J. Med. Sci. 27, 656–658 (1991).

    CAS  Google Scholar 

  26. Milner, I. B. & Axelrod, B. N., Pasquantonio, J. & Sillanpaa, M. Is there a Gulf War syndrome? J. Am. Med. Assoc. 271, 661 (1994).

    Article  CAS  Google Scholar 

  27. Friedman, A. & Gutnick, M. J. Intracellular calcium and control of burst generation in neurons of guinea-pig neocortex in vitro. Eur. J. Neurosci. 1, 374–381 (1989).

    Article  Google Scholar 

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Acknowledgements

We thank M. J. Gutnick for inspiration and discussion, and M. Sternfeld for recombinant cholinesterase variants. This research was supported by grants from the US Army Medical Research and Development Command, the Israel Science Fund, the USA–Israel Binational Science Foundation, the Israeli Health Ministry and Ester/Medica Neuroscience (to H.S.). A.F. was a post-doctoral fellow of the Smith Psychobiology Fund and an incumbent of the Teva research prize for young investigators.

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  1. Department of Biological Chemistry, The Alexander Silberman Life Sciences Institute, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel

    Daniela Kaufer, Alon Friedman, Shlomo Seidman & Hermona Soreq

  2. Departments of Physiology and Neurosurgery, Faculty of Health Science, and Zlotowski Center for Neuroscience, Ben Gurion University, 84105, Beersheva, Israel

    Alon Friedman

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  1. Daniela Kaufer
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Correspondence to Hermona Soreq.

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Kaufer, D., Friedman, A., Seidman, S. et al. Acute stress facilitates long-lasting changes in cholinergic gene expression. Nature 393, 373–377 (1998). https://doi.org/10.1038/30741

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