Abstract
NMDA-type glutamate receptors play a critical role in the activity-dependent development and structural remodeling of dendritic arbors and spines. However, the molecular mechanisms that link NMDA receptor activation to changes in dendritic morphology remain unclear. We report that the Rac1-GEF Tiam1 is present in dendrites and spines and is required for their development. Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation. Blockade of Tiam1 function with RNAi and dominant interfering mutants of Tiam1 suggests that Tiam1 mediates effects of the NMDA receptor on dendritic development by inducing Rac1-dependent actin remodeling and protein synthesis. Taken together, these findings define a molecular mechanism by which NMDA receptor signaling controls the growth and morphology of dendritic arbors and spines.
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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6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Brain / cytology
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Brain / metabolism
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Calcium / metabolism
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Cell Line
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Cell Size / drug effects
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Cloning, Molecular / methods
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism
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Dendritic Spines / physiology*
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Dendritic Spines / ultrastructure
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Drug Interactions
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Egtazic Acid / pharmacology
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Ephrin-B1 / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Gene Expression Regulation, Developmental / drug effects
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Gene Expression Regulation, Developmental / physiology
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Glutamic Acid / pharmacology
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Green Fluorescent Proteins / metabolism
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Guanine Nucleotide Exchange Factors
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Humans
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Immunohistochemistry / methods
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Immunoprecipitation / methods
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Microscopy, Immunoelectron / methods
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Models, Neurological
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Neoplasm Proteins
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proteins / antagonists & inhibitors
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Proteins / metabolism*
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RNA, Antisense / pharmacology
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RNA, Small Interfering
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Rats
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Receptors, N-Methyl-D-Aspartate / agonists
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Receptors, N-Methyl-D-Aspartate / classification
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Synaptosomes / metabolism
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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Tetrodotoxin / pharmacology
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Time Factors
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Transfection / methods
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Valine / analogs & derivatives*
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Valine / pharmacology
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p21-Activated Kinases
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rac1 GTP-Binding Protein / metabolism*
Substances
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DNA-Binding Proteins
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ELF4 protein, human
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Ephrin-B1
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Excitatory Amino Acid Antagonists
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Guanine Nucleotide Exchange Factors
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Neoplasm Proteins
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Proteins
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RNA, Antisense
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RNA, Small Interfering
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Receptors, N-Methyl-D-Aspartate
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SLC2A4RG protein, human
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T-Lymphoma Invasion and Metastasis-inducing Protein 1
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TIAM1 protein, human
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Tiam1 protein, rat
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Transcription Factors
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Green Fluorescent Proteins
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Glutamic Acid
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Tetrodotoxin
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Egtazic Acid
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6-Cyano-7-nitroquinoxaline-2,3-dione
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2-amino-5-phosphopentanoic acid
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Protein Serine-Threonine Kinases
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p21-Activated Kinases
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rac1 GTP-Binding Protein
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Valine
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Calcium