Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Behavior, Animal
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Blotting, Northern / methods
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Blotting, Western / methods
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Dendrites / pathology
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Drug Interactions
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Enzyme Activation
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Glycine / pharmacology
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Hippocampus / pathology
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Hippocampus / physiopathology
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Hippocampus / ultrastructure
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Immunohistochemistry / methods
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In Situ Hybridization / methods
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Long-Term Potentiation
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Long-Term Synaptic Depression
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Male
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Maze Learning / physiology
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Memory Disorders / genetics
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Memory Disorders / pathology*
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Memory Disorders / physiopathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Microscopy, Electron / methods
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Models, Neurological
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Nerve Tissue Proteins / drug effects
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology
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Neurofilament Proteins / metabolism
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Neurons / classification
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Neurons / pathology
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Neurons / ultrastructure
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Prosencephalon / pathology*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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Proto-Oncogene Proteins c-myc / metabolism
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Rats
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Retention, Psychology / drug effects
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Silver Staining / methods
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Spatial Behavior / physiology
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Synapses / pathology*
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Synaptophysin / metabolism
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Time Factors
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Valine / analogs & derivatives*
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Valine / pharmacology
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
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p21-Activated Kinases
Substances
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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Nerve Tissue Proteins
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Neurofilament Proteins
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Proto-Oncogene Proteins c-myc
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Synaptophysin
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postsynaptic density proteins
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neurofilament protein M
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2-amino-5-phosphopentanoic acid
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alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
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Pak3 protein, mouse
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Pak3 protein, rat
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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Valine
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Glycine