Acetylcholine-induced seizure-like activity and modified cholinergic gene expression in chronically epileptic rats

Authors

  • Gabriel Zimmerman,

    1. Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, 91904 Israel
    2. Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Israel
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  • Marleisje Njunting,

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
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  • Sebastian Ivens,

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
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  • Elsa Tolner,

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
    2. Department of Biological and Environmental Sciences, University of Helsinki, PO Box 65 (Viikinkaari 1), 00014 Helsinki, Finland
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  • Christoph J. Behrens,

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
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  • Miriam Gross,

    1. Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Israel
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  • Hermona Soreq,

    1. Interdisciplinary Center for Neural Computation, The Hebrew University of Jerusalem, 91904 Israel
    2. Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Israel
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  • Uwe Heinemann,

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
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  • Alon Friedman

    1. Institute for Neurophysiology, University Medicine Berlin, 10117 Germany
    2. Departments of Physiology and Neurosurgery, Zlotowski Center of Neuroscience, Ben-Gurion University, Beer-Sheva, 84105 Israel
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Errata

This article is corrected by:

  1. Errata: Acetylcholine-induced seizure-like activity and modified cholinergic gene expression in chronically epileptic rats Volume 28, Issue 2, 418, Article first published online: 15 July 2008

Dr A. Friedman, as above.5
E-mail: alonf@bgu.ac.il

Abstract

The entorhinal cortex (EC) plays an important role in temporal lobe epilepsy. Under normal conditions, the enriched cholinergic innervation of the EC modulates local synchronized oscillatory activity; however, its role in epilepsy is unknown. Enhanced neuronal activation has been shown to induce transcriptional changes of key cholinergic genes and thus alter cholinergic responses. To examine cholinergic modulations in epileptic tissue we studied molecular and electrophysiological cholinergic responses in the EC of chronically epileptic rats following exposure to pilocarpine or kainic acid. We confirmed that while the total activity of the acetylcholine (ACh)-hydrolysing enzyme, acetylcholinesterase (AChE) was not altered, epileptic rats showed alternative splicing of AChE pre-mRNA transcripts, accompanied by a shift from membrane-bound AChE tetramers to soluble monomers. This was associated with increased sensitivity to ACh application: thus, in control rats, ACh (10–100 µm) induced slow (< 1Hz), periodic events confined to the EC; however, in epileptic rats, ACh evoked seconds-long seizure-like events with initial appearance in the EC, and frequent propagation to neighbouring cortical regions. ACh-induced seizure-like events could be completely blocked by the non-specific muscarinic antagonist, atropine, and were partially blocked by the muscarinic-1 receptor antagonist, pirenzepine; but were not affected by the non-specific nicotinic antagonist, mecamylamine. Epileptic rats presented reduced transcript levels of muscarinic receptors with no evidence of mRNA editing or altered mRNA levels for nicotinic ACh receptors. Our findings suggest that altered cholinergic modulation may initiate seizure events in the epileptic temporal cortex.

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