Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory
Open accessAbstract
While deregulation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neurodegenerative diseases, its precise role in synaptic plasticity and memory remains elusive. Proteolytic cleavage of p35, a regulatory subunit of Cdk5, by calpain results in the generation of the truncated p25 protein, which causes hyperactivation of Cdk5. Using region-specific and inducible transgenic mice, we show that transiently increased p25 expression in the hippocampus enhanced long-term potentiation (LTP) and facilitated hippocampus-dependent memory. Moreover, p25 expression increased the number of dendritic spines and synapses. Importantly, enhanced memory achieved by a transient expression of p25 followed by its repression did not cause neurodegeneration. In contrast, prolonged p25 production caused severe cognitive deficits, which were accompanied by synaptic and neuronal loss and impaired LTP. Our data suggest a role for p25 in synaptic plasticity, synaptogenesis, learning, and memory and provide a model whereby deregulation of a plasticity factor can contribute to neurodegeneration.
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A11 treatment improved performance of CK-p25 mice in the Y maze, increasing novel arm preference above chance from −4.1 ± 9.4% in vehicle-injected mice to 18.7 ± 11.7% in A11-injected mice (P = 0.0007).
“A11 treatment improved performance of CK-p25 mice in the Y maze (Cruz et al., 2003; Fischer et al., 2005), increasing the novel arm preference above chance from −4.1 ± 9.4% in vehicle-injected mice to 18.7 ± 11.7% to in A11-injected mice (P = 0.0007; left panel of Fig. 4 i).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Fischer et al., 2005
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“This would be analogous to the opposing effects of transient versus prolonged activation of Cdk5 on synaptic plasticity and hippocampus-dependent memory (Fischer et al., 2005).”
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- Authors
- Fischer, A., Sananbenesi, F., Pang, P. T., Lu, B., & Tsai, L.-H.
- Affiliations
- Harvard University (US)
- National Institutes of Health (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tsai, Li-Huei
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 48
- Issue
- 5
- Pages
- 825-838
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2159663149
- Cited by
- 277
- References
- 57
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 8 · 2020: 7 · 2019: 16 · 2018: 9 · 2017: 15 · 2016: 8 · 2015: 15 · 2014: 21 · 2013: 15 · 2012: 19
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2785 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- GRO (submittedVersion)
- Funders
- National Institutes of Health (NS051874)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- p25, cyclin-dependent kinase 5, calpain, long-term potentiation, synaptic plasticity, hippocampal-dependent memory, dendritic spines, synaptogenesis, cognitive impairment, neurodegeneration
- MeSH terms
- Animals, Anxiety, Association Learning, Cognition Disorders, Conditioning, Psychological, Dendrites, Fear, Hippocampus, Learning, Memory, Mice, Transgenic, Nerve Degeneration, Nerve Tissue Proteins, Neuronal Plasticity, Phosphotransferases, Space Perception, Swimming, Synapses, Time Factors, Maze Learning, Mice
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