Upregulation of CREB-Mediated Transcription Enhances Both Short- and Long-Term Memory
Open accessAbstract
Unraveling the mechanisms by which the molecular manipulation of genes of interest enhances cognitive function is important to establish genetic therapies for cognitive disorders. Although CREB is thought to positively regulate formation of long-term memory (LTM), gain-of-function effects of CREB remain poorly understood, especially at the behavioral level. To address this, we generated four lines of transgenic mice expressing dominant active CREB mutants (CREB-Y134F or CREB-DIEDML) in the forebrain that exhibited moderate upregulation of CREB activity. These transgenic lines improved not only LTM but also long-lasting long-term potentiation in the CA1 area in the hippocampus. However, we also observed enhanced short-term memory (STM) in contextual fear-conditioning and social recognition tasks. Enhanced LTM and STM could be dissociated behaviorally in these four lines of transgenic mice, suggesting that the underlying mechanism for enhanced STM and LTM are distinct. LTM enhancement seems to be attributable to the improvement of memory consolidation by the upregulation of CREB transcriptional activity, whereas higher basal levels of BDNF, a CREB target gene, predicted enhanced shorter-term memory. The importance of BDNF in STM was verified by microinfusing BDNF or BDNF inhibitors into the hippocampus of wild-type or transgenic mice. Additionally, increasing BDNF further enhanced LTM in one of the lines of transgenic mice that displayed a normal BDNF level but enhanced LTM, suggesting that upregulation of BDNF and CREB activity cooperatively enhances LTM formation. Our findings suggest that CREB positively regulates memory consolidation and affects memory performance by regulating BDNF expression.
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BDNF plays roles in plasticity and cognitive improvement.
“BDNF plays roles in plasticity and cognitive improvement.”
From 2-Deoxyglucose drives plasticity via an adaptive ER stress-ATF4 pathway and elicits stroke recovery and Alzheimer’s resilience (2023) · cites this paper as [26]
The section on BDNF’s contribution to long-term memory reports that hippocampal BDNF infusion improved recognition memory in mice, supporting a role in cognitive improvement. The paper also reports enhanced long-term potentiation in active-CREB mice, but the cited passages do not establish that BDNF itself caused that change in plasticity. (LLM, conf=0.83)
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- Authors
- Suzuki, A., Fukushima, H., Mukawa, T., Toyoda, H., Wu, L.-J., Zhao, M.-G., Xu, H., Shang, Y., Endoh, K., Iwamoto, T., Mamiya, N., Okano, E., Hasegawa, S., Mercaldo, V., Zhang, Y., Maeda, R., Ohta, M., Josselyn, S. A., Zhuo, M., & Kida, S.
- Affiliations
- Tokyo University of Agriculture (JP)
- University of Toronto (CA)
- ORCID
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-06-15
- Volume
- 31
- Issue
- 24
- Pages
- 8786-8802
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6622960
- OpenAlex
- W2006914006
- Cited by
- 250
- References
- 62
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 16 · 2023: 16 · 2022: 16 · 2021: 16 · 2020: 12 · 2019: 21 · 2018: 14 · 2017: 16 · 2016: 22 · 2015: 27 · 2014: 21 · 2013: 16 · 2012: 19
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Sumitomo Foundation
- Canadian Institutes of Health Research (66975)
- Japan Society for the Promotion of Science (23115716), 23300120, 23659318)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- CREB, long-term memory, short-term memory, memory consolidation, brain-derived neurotrophic factor, hippocampus, CA1, long-term potentiation, contextual fear conditioning, social recognition, transgenic mice, gain-of-function
- MeSH terms
- Analysis of Variance, Animals, Bacterial Proteins, Behavior, Animal, Carbazoles, Cell Line, Transformed, Chlorocebus aethiops, Conditioning, Classical, Discrimination, Psychological, Electric Stimulation, Enzyme Inhibitors, Fear, Hippocampus, Luminescent Proteins, Memory, Short-Term, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Phenylalanine, RNA, Messenger, Social Behavior, Transfection, Tyrosine, Up-Regulation, Long-Term Potentiation, Cyclic AMP-Dependent Protein Kinases, Patch-Clamp Techniques, Maze Learning, Brain-Derived Neurotrophic Factor, Excitatory Postsynaptic Potentials, Indole Alkaloids, Fluorescence Resonance Energy Transfer, CREB-Binding Protein, Mice, Rats, Calcium-Calmodulin-Dependent Protein Kinase Type 4, Memory, Long-Term
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