Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex

Takeo Saneyoshi, Gary Wayman, Dale Fortin, Monika Davare, Naoto Hoshi, Naohito Nozaki, Tohru Natsume, Thomas R. Soderling

Research output: Contribution to journalArticle

158 Scopus citations

Abstract

Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca2+-signaling pathway downstream of the NMDA receptor that stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI to promote formation of spines and synapses in hippocampal neurons. CaMKK and CaMKI form a multiprotein signaling complex with the guanine nucleotide exchange factor (GEF) βPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in βPIX enhances its GEF activity, resulting in activation of Rac1, an established enhancer of spinogenesis. Suppression of CaMKK or CaMKI by pharmacological inhibitors, dominant-negative (dn) constructs and siRNAs, as well as expression of the βPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or βPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity.

Original languageEnglish (US)
Pages (from-to)94-107
Number of pages14
JournalNeuron
Volume57
Issue number1
DOIs
StatePublished - Jan 10 2008

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Keywords

  • CELLBIO
  • MOLNEURO
  • SIGNALING

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Saneyoshi, T., Wayman, G., Fortin, D., Davare, M., Hoshi, N., Nozaki, N., Natsume, T., & Soderling, T. R. (2008). Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex. Neuron, 57(1), 94-107. https://doi.org/10.1016/j.neuron.2007.11.016