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Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation
Open accessAbstract
Stress insults intensify fear memory; however, the mechanism(s) facilitating this physiological response is still unclear. Here, we report the molecular, neurophysiological and behavioral findings attributing much of this effect to alternative splicing of the acetylcholinesterase (AChE) gene in hippocampal neurons. As a case study, we explored immobilization-stressed mice with intensified fear memory and enhanced long-term potentiation (LTP), in which alternative splicing was found to induce overproduction of neuronal 'readthrough' AChE-R (AChE-R). Selective downregulation of AChE-R mRNA and protein by antisense oligonucleotides abolished the stress-associated increase in AChE-R, the elevation of contextual fear and LTP in the hippocampal CA1 region. Reciprocally, we intrahippocampally injected a synthetic peptide representing the C-terminal sequence unique to AChE-R. The injected peptide, which has been earlier found to exhibit no enzymatic activity, was incorporated into cortical, hippocampal and basal nuclei neurons by endocytosis and retrograde transport and enhanced contextual fear. Compatible with this hypothesis, inherited AChE-R overexpression in transgenic mice resulted in perikaryal clusters enriched with PKCbetaII, accompanied by PKC-augmented LTP enhancement. Our findings demonstrate a primary role for stress-induced alternative splicing of the AChE gene to elevated contextual fear and synaptic plasticity, and attribute to the AChE-R splice variant a major role in…
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“The ability of ACh to induce synaptic plasticity through actions on pre- and post-synaptic nAChRs and mAChRs is likely to modulate learning and memory, including memory of stressful events (Nijholt et al., 2004)”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Nijholt et al., 2004
In the citing paper
“Stress also induces alternative splicing of the AChE mRNA in the hippocampus leading to altered ACh signaling in this structure (Nijholt et al., 2004).”
From Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior (2012) · cites this paper as Nijholt et al., 2004
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“Compatible with this hypothesis, inherited AChE-R overexpression in transgenic mice resulted in perikaryal clusters enriched with PKCbII, accompanied by PKCaugmented LTP enhancement. Our findings demonstrate a primary role for stress-induced alternative splicing of the AChE gene to elevated contextual fear and synapti…”
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Sorted by citations
Acetylcholine as a Neuromodulator: Cholinergic Signaling Shapes Nervous System Function and Behavior
Picciotto, M. R., Higley, M. J., & Mineur, Y. S. (2012) · Neuron · doi:10.1016/j.neuron.2012.08.036 · Cited by 1,404
“Stress also induces alternative splicing of the AChE messenger RNA (mRNA) in the hippocampus, leading to altered ACh signaling in this structure (Nijholt et al., 2004).”
BackgroundStress effects in the hippocampus: Synaptic plasticity and memory
Kim, J. J., Song, E. Y., Kim, J. J., Song, E. Y., & Kosten, T. A. (2006) · Stress · doi:10.1080/10253890600678004 · Cited by 261
“Recent studies have reported that stress enhances hippocampal-dependent aversive tasks (i.e. trace eyeblink conditioning and contextual fear conditioning) (Beylin and Shors 1998; Nijholt et al. 2004).”
BackgroundChapter 8 Synaptic plasticity in learning and memory: Stress effects in the hippocampus
Howland, J. G., & Wang, Y. T. (2008) · Progress in brain research · doi:10.1016/s0079-6123(07)00008-8 · Cited by 243
“Interestingly, acute stress also enhances memory in aversive hippocampal-dependent tasks such as contextual fear conditioning and trace eye-blink conditioning (Beylin and Shors, 1998; Nijholt et al., 2004), thereby demonstrating that the effects of stress may differ in aversively motivated contexts.”
BackgroundCholinergic regulation of mood: from basic and clinical studies to emerging therapeutics
Dulawa, S. C., & Janowsky, D. S. (2019) · Molecular Psychiatry · doi:10.1038/s41380-018-0219-x · Cited by 187
“Furthermore, stress induces alternative splicing of AChE mRNAs and modulation of AChE activity 82, 83 .”
BackgroundNeuromodulation by acetylcholine: examples from schizophrenia and depression
Higley, M. J., & Picciotto, M. R. (2014) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.06.004 · Cited by 184
“Exposure to an acute stress may lead to adaptive behavioral responses mediated through ACh release in the hippocampus, whereas chronic increases in ACh signaling can lead to mood disorders, perhaps by evoking synaptic plasticity in different neuronal subtypes throughout the hippocampus [88] and contributing to encodin…”
Metadata
- Authors
- Nijholt, I., Farchi, N., Kye, M., Sklan, E. H., Shoham, S., Verbeure, B., Owen, D., Hochner, B., Spiess, J., Soreq, H., & Blank, T.
- Affiliations
- Max Planck Institute of Experimental Medicine (DE)
- Hebrew University of Jerusalem (IL)
- Herzog Hospital (IL)
- MRC Laboratory of Molecular Biology (GB)
- Corresponding author
- Blank, T
- Venue
- Molecular Psychiatry
- Published
- 2003-10-28
- Volume
- 9
- Issue
- 2
- Pages
- 174-183
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- OpenAlex
- W2165828523
- Cited by
- 126
- References
- 43
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 3 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 10 · 2012: 10
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Max-Planck-Gesellschaft
- Medical Research and Materiel Command
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- acetylcholinesterase, alternative splicing, stress, fear memory, long-term potentiation, hippocampus, CA1, antisense oligonucleotides, contextual fear, PKCβII, synaptic plasticity, restraint stress, transgenic mice
- MeSH terms
- Acetylcholinesterase, Animals, Fear, Hippocampus, Memory, Neuronal Plasticity, Protein Kinase C, RNA, Messenger, Stress, Physiological, Gene Expression Regulation, Enzymologic, Alternative Splicing, Long-Term Potentiation, Mice, Protein Kinase C beta
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