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Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain- Specific Dominant-Negative PAK Transgenic Mice
Open accessAbstract
Molecular and cellular mechanisms for memory consolidation in the cortex are poorly known. To study the relationships between synaptic structure and function in the cortex and consolidation of long-term memory, we have generated transgenic mice in which catalytic activity of PAK, a critical regulator of actin remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these mice displayed fewer dendritic spines and an increased proportion of larger synapses compared to wild-type controls. These alterations in basal synaptic morphology correlated with enhanced mean synaptic strength and impaired bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the cortex. By contrast, spine morphology and synaptic plasticity were normal in the hippocampus of these mice. Importantly, these mice exhibited specific deficits in the consolidation phase of hippocampus-dependent memory. Thus, our results provide evidence for critical relationships between synaptic morphology and bidirectional modifiability of synaptic strength in the cortex and consolidation of long-term memory.
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“Moreover, alterations in the regulation of actin at dendritic spines, by neurodevelopmental disease-associated proteins such as DISC1, DTNBP1, SHANK3, PAK3, Oligophrenin and SRGAP2, have been shown to produce deficits in both synaptic plasticity and the formation and consolidation of long-term memories.23, 24, 25, 26, 27, 28, 29”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [26]
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“Our results suggest that CYFIP1 is part of a growing number of mental illness-associated actin-regulatory molecules, including DISC1, DTNBP1, SHANK3, SRGAP2, Oligophrenin and the Abi1-WAVE2 complex that act in Rac1-dependent pathways to regulate dendritic development and spine dynamics.24, 25, 26, 27, 28, 29”
From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [26]
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Metadata
- Authors
- Hayashi, M. L., Choi, S.-Y., Rao, B. S. S., Jung, H.-Y., Lee, H.-K., Zhang, D., Chattarji, S., Kirkwood, A., & Tonegawa, S.
- Affiliations
- Howard Hughes Medical Institute (US)
- Johns Hopkins University (US)
- Tata Institute of Fundamental Research (IN)
- Corresponding author
- Tonegawa, Susumu
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2004-06
- Volume
- 42
- Issue
- 5
- Pages
- 773-787
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2006423839
- Cited by
- 280
- References
- 87
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 5 · 2022: 7 · 2021: 6 · 2020: 6 · 2019: 11 · 2018: 7 · 2017: 14 · 2016: 19 · 2015: 7 · 2014: 22 · 2013: 19 · 2012: 13
- FWCI
- 6.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- p21-activated kinase, dendritic spines, memory consolidation, long-term memory, synaptic plasticity, long-term potentiation, long-term depression, actin cytoskeleton remodeling, hippocampal-dependent memory
- MeSH terms
- Analysis of Variance, Animals, Animals, Newborn, Behavior, Animal, Dendrites, Drug Interactions, Enzyme Activation, Glycine, Hippocampus, Immunohistochemistry, Male, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Models, Neurological, Nerve Tissue Proteins, Neurons, Retention, Psychology, Spatial Behavior, Synapses, Time Factors, Valine, Blotting, Northern, Blotting, Western, Proto-Oncogene Proteins c-myc, Prosencephalon, Silver Staining, Synaptophysin, Neurofilament Proteins, Protein Serine-Threonine Kinases, In Situ Hybridization, Long-Term Potentiation, alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Excitatory Amino Acid Agonists, Excitatory Amino Acid Antagonists, Maze Learning, Long-Term Synaptic Depression, Mice, Rats, p21-Activated Kinases
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