Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain- Specific Dominant-Negative PAK Transgenic Mice
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 regulato...
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| Veröffentlicht in: | Neuron (Cambridge, Mass.) Mass.), 2004-06, Vol.42 (5), p.773-787 |
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| creator | Hayashi, Mansuo L Choi, Se-Young Rao, B.S.Shankaranarayana Jung, Hae-Yoon Lee, Hey-Kyoung Zhang, Dawei Chattarji, Sumantra Kirkwood, Alfredo Tonegawa, Susumu |
| description | 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. |
| doi_str_mv | 10.1016/j.neuron.2004.05.003 |
| format | Article |
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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. 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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. 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Choi, Se-Young ; Rao, B.S.Shankaranarayana ; Jung, Hae-Yoon ; Lee, Hey-Kyoung ; Zhang, Dawei ; Chattarji, Sumantra ; Kirkwood, Alfredo ; Tonegawa, Susumu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-44af87c9ba146110936cec6969386866a88b183be2e15b2755d75183768050853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Animals, Newborn</topic><topic>Behavior, Animal</topic><topic>Blotting, Northern - methods</topic><topic>Blotting, Western - methods</topic><topic>Dendrites - pathology</topic><topic>Drug Interactions</topic><topic>Enzyme Activation</topic><topic>Excitatory Amino Acid Agonists - pharmacology</topic><topic>Excitatory Amino Acid Antagonists - pharmacology</topic><topic>Glycine - pharmacology</topic><topic>Hippocampus - pathology</topic><topic>Hippocampus - physiopathology</topic><topic>Hippocampus - ultrastructure</topic><topic>Immunohistochemistry - methods</topic><topic>In Situ Hybridization - methods</topic><topic>Kinases</topic><topic>Long-Term Potentiation</topic><topic>Long-Term Synaptic Depression</topic><topic>Male</topic><topic>Maze Learning - physiology</topic><topic>Memory Disorders - genetics</topic><topic>Memory Disorders - pathology</topic><topic>Memory Disorders - physiopathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Microscopy, Electron - methods</topic><topic>Models, Neurological</topic><topic>Nerve Tissue Proteins - drug effects</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Nerve Tissue Proteins - physiology</topic><topic>Neurofilament Proteins - metabolism</topic><topic>Neurons - classification</topic><topic>Neurons - pathology</topic><topic>Neurons - ultrastructure</topic><topic>p21-Activated Kinases</topic><topic>Prosencephalon - pathology</topic><topic>Protein-Serine-Threonine Kinases - genetics</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-myc - metabolism</topic><topic>Rats</topic><topic>Retention (Psychology) - drug effects</topic><topic>Rodents</topic><topic>Silver Staining - methods</topic><topic>Spatial Behavior - physiology</topic><topic>Studies</topic><topic>Synapses - pathology</topic><topic>Synaptophysin - metabolism</topic><topic>Time Factors</topic><topic>Valine - analogs & derivatives</topic><topic>Valine - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hayashi, Mansuo L</creatorcontrib><creatorcontrib>Choi, Se-Young</creatorcontrib><creatorcontrib>Rao, B.S.Shankaranarayana</creatorcontrib><creatorcontrib>Jung, Hae-Yoon</creatorcontrib><creatorcontrib>Lee, Hey-Kyoung</creatorcontrib><creatorcontrib>Zhang, Dawei</creatorcontrib><creatorcontrib>Chattarji, Sumantra</creatorcontrib><creatorcontrib>Kirkwood, Alfredo</creatorcontrib><creatorcontrib>Tonegawa, Susumu</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Neuron (Cambridge, Mass.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hayashi, Mansuo L</au><au>Choi, Se-Young</au><au>Rao, B.S.Shankaranarayana</au><au>Jung, Hae-Yoon</au><au>Lee, Hey-Kyoung</au><au>Zhang, Dawei</au><au>Chattarji, Sumantra</au><au>Kirkwood, Alfredo</au><au>Tonegawa, Susumu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain- Specific Dominant-Negative PAK Transgenic Mice</atitle><jtitle>Neuron (Cambridge, Mass.)</jtitle><addtitle>Neuron</addtitle><date>2004-06-10</date><risdate>2004</risdate><volume>42</volume><issue>5</issue><spage>773</spage><epage>787</epage><pages>773-787</pages><issn>0896-6273</issn><eissn>1097-4199</eissn><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. 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| subjects | alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology Analysis of Variance Animals Animals, Newborn Behavior, Animal Blotting, Northern - methods Blotting, Western - methods Dendrites - pathology Drug Interactions Enzyme Activation Excitatory Amino Acid Agonists - pharmacology Excitatory Amino Acid Antagonists - pharmacology Glycine - pharmacology Hippocampus - pathology Hippocampus - physiopathology Hippocampus - ultrastructure Immunohistochemistry - methods In Situ Hybridization - methods Kinases Long-Term Potentiation Long-Term Synaptic Depression Male Maze Learning - physiology Memory Disorders - genetics Memory Disorders - pathology Memory Disorders - physiopathology Mice Mice, Inbred C57BL Mice, Transgenic Microscopy, Electron - methods Models, Neurological Nerve Tissue Proteins - drug effects Nerve Tissue Proteins - metabolism Nerve Tissue Proteins - physiology Neurofilament Proteins - metabolism Neurons - classification Neurons - pathology Neurons - ultrastructure p21-Activated Kinases Prosencephalon - pathology Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Proteins Proto-Oncogene Proteins c-myc - metabolism Rats Retention (Psychology) - drug effects Rodents Silver Staining - methods Spatial Behavior - physiology Studies Synapses - pathology Synaptophysin - metabolism Time Factors Valine - analogs & derivatives Valine - pharmacology |
| title | Altered Cortical Synaptic Morphology and Impaired Memory Consolidation in Forebrain- Specific Dominant-Negative PAK Transgenic Mice |
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