Public Release: 

Avoid bad memories: Targeting genes and drugs

Molecular Psychiatry

We all remember September 11, 2001, only too well; this is because our brain etches fearful memories deep into our system. This property can provide selection advantages to creatures that can learn to avoid fearful situations and improve their chances to survive in a dangerous world. However, the intensification of fearful memories sometimes charges a high toll. Patients with Post-Traumatic Stress Disorder, for example, can never forget the traumatic experience they went through. Just hearing a bus horn may throw them back into the battle they wish to forget, and they will freeze in response and loose contact with their surroundings. It is clearly of much significance to unravel the genes and proteins that are responsible for such responses; once this is achieved, the door will be opened for developing rationally designed therapeutic treatments for down tuning the fierce impact of traumatic memories.

With these goals in mind, a joint team of researchers at the Max Planck Institute for Experimental Medicine in Gottingen, Germany and at The Hebrew University of Jerusalem in Israel explored memory processes in mice following immobilization stress. In their learning and memory model, mice learn to associate a fearful event with its context. Immobilization stress before subjecting mice to the learning paradigm will let the mice remember this context better; once they are back in the fearful environment, they stop moving, they "freeze". In parallel, stress leads to a change in brain neurons' gene expression. One specific change involves the acetylcholinesterase gene, which normally produces a protein product that adheres to synapses (the interaction sites through which nerve cells communicate with each other). Following stress, the same gene produces large quantities of a secretory protein with modified properties.

The effects of the observed changes in gene functioning were also tested. This involved measuring neuronal electrical signals. In the current study, the research team found that the change in acetylcholinesterase leads to elevated neuronal signaling in the brain of stressed animals. Taking advantage of the technology of transgenic engineering, the researchers have further examined a transgenic mouse with chronic stress-like change in gene expression. This mouse as well displayed potentiated electrical signals, which are highly relevant to learning and memory.

Finally, the research team worked to prove their new findings by trying to prevent the changes in gene expression from occurring. This involved the use of a new gene-based "antisense" drug, inversely oriented to the stress-induced gene product. Such drugs cause destruction of their target molecule, preventing further consequences of the accumulated molecule from taking place. Injection of the acetylcholinesterase-targeted antisense agent to the brain of mice prior to the stress exposure suppressed the change in gene expression, prevented neuronal intensified signaling and attenuated the elevated freezing response, proving that the detected change was causally involved with the behavioral impact and paving the way toward developing novel treatment to traumatized patients.

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Citation source: Molecular Psychiatry advance online publication, December 2003 (doi:10.1038/sj.mp.4001446)

ARTICLE: "Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation"

AUTHORS: Ingrid Nijholt, Noa Farchi, Min-Jeong Kye, Ella H. Sklan, Shai Shoham, Birgit Verbeure, David Owen, Binyamin Hochner, Joachim Spiess, Hermona Soreq, Thomas Blank

Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Goettingen, Germany; Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, Israel; Department of Neurobiology, The Institute of Life Sciences, The Hebrew University of Jerusalem, Israel; 4Research Department, Herzog Hospital, Jerusalem, Israel; 5MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK

For further information on this work, please contact Dr. Thomas Blank, Department of Molecular Neuroendocrinology, Max Planck Institute for Experimental Medicine, Hermann-Rein-Str. 3, D-37075, Goettingen, Germany. Phone: 49-551-3899-406/40; Fax:: 49-551-3899-359, Email: blank@em.mpg.de

Molecular Psychiatry is published by the Nature Publishing Group. http://www.nature.com/mp

Editor: Julio Licinio, M.D.; phone: 310-825-7113; FAX: 310-206-6715; e-mail: licinio@ucla.edu

For a copy of this article, please contact Aimee Midei, Editorial Assistant, e-mail:molecularpsychiatry@mednet.ucla.edu.

PLEASE CITE MOLECULAR PSYCHIATRY AS THE SOURCE OF THIS MATERIAL.

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