Activity-Dependent Growth of New Dendritic Spines Is Regulated by the Proteasome

Andrew M. Hamilton, Won Chan Oh, Hugo Vega-Ramirez, Ivar S. Stein, Johannes W Hell, Gentry N. Patrick, Karen Zito

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

Growth of new dendritic spines contributes to experience-dependent circuit plasticity in the cerebral cortex. Yet the signaling mechanisms leading to new spine outgrowth remain poorly defined. Increasing evidence supports that the proteasome is an important mediator of activity-dependent neuronal signaling. We therefore tested the role of the proteasome in activity-dependent spinogenesis. Using pharmacological manipulations, glutamate uncaging, and two-photon imaging of GFP-transfected hippocampal pyramidal neurons, we demonstrate that acute inhibition of the proteasome blocks activity-induced spine outgrowth. Remarkably, mutation of serine 120 to alanine of the Rpt6 proteasomal subunit in individual neurons was sufficient to block activity-induced spine outgrowth. Signaling through NMDA receptors and CaMKII, but not PKA, is required to facilitate spine outgrowth. Moreover, abrogating CaMKII binding to the NMDA receptor abolished activity-induced spinogenesis. Our data support a model in which neural activity facilitates spine outgrowth via an NMDA receptor- and CaMKII-dependent increase in local proteasomal degradation.

Original languageEnglish (US)
Pages (from-to)1023-1030
Number of pages8
JournalNeuron
Volume74
Issue number6
DOIs
StatePublished - Jun 21 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Hamilton, A. M., Oh, W. C., Vega-Ramirez, H., Stein, I. S., Hell, J. W., Patrick, G. N., & Zito, K. (2012). Activity-Dependent Growth of New Dendritic Spines Is Regulated by the Proteasome. Neuron, 74(6), 1023-1030. https://doi.org/10.1016/j.neuron.2012.04.031