The Rac1-GEF Tiam1 Couples the NMDA Receptor to the Activity-Dependent Development of Dendritic Arbors and Spines

• Published in: Neuron (Cambridge, Mass.) Mass.), 2005-02, Vol.45 (4), p.525-538
• Main Authors: Tolias, Kimberley F., Bikoff, Jay B., Burette, Alain, Paradis, Suzanne, Harrar, Dana, Tavazoie, Sohail, Weinberg, Richard J., Greenberg, Michael E.
• Format: Article
• Language: English
• Subjects: 6-Cyano-7-nitroquinoxaline-2,3-dione - pharmacology; Animals; Animals, Newborn; Blotting, Western - methods; Brain; Brain - cytology; Brain - metabolism; Brain research; Calcium - metabolism; Cell culture; Cell Line; Cell Size - drug effects; Cloning, Molecular - methods; Cytoskeleton; Dendritic Spines - physiology; Dendritic Spines - ultrastructure; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - metabolism; Drug Interactions; Egtazic Acid - pharmacology; Ephrin-B1 - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Gene expression; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - physiology; Glutamic Acid - pharmacology; Green Fluorescent Proteins - metabolism; Guanine Nucleotide Exchange Factors; Humans; Immunohistochemistry - methods; Immunoprecipitation - methods; Kinases; Medical research; Microscopy; Microscopy, Immunoelectron - methods; Models, Neurological; Morphogenesis; Neoplasm Proteins; Neurons; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; p21-Activated Kinases; Protein-Serine-Threonine Kinases - metabolism; Proteins - antagonists & inhibitors; Proteins - metabolism; rac1 GTP-Binding Protein - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - agonists; Receptors, N-Methyl-D-Aspartate - classification; Receptors, N-Methyl-D-Aspartate - metabolism; RNA, Antisense - pharmacology; RNA, Small Interfering; Rodents; Synaptosomes - metabolism; T-Lymphoma Invasion and Metastasis-inducing Protein 1; Tetrodotoxin - pharmacology; Time Factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Transfection - methods; Valine - analogs & derivatives; Valine - pharmacology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2005.01.024

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.