Activity-dependent growth of new dendritic spines is regulated by the proteasome.
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.
Center for Neuroscience, University of California Davis, Davis, CA 95616, USA.
Andrew M
AM
Hamilton
Won Chan
WC
Oh
Hugo
H
Vega-Ramirez
Ivar S
IS
Stein
Johannes W
JW
Hell
Gentry N
GN
Patrick
Karen
K
Zito
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000378:metabolism; D014162:Transfection
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D016194:Receptors, N-Methyl-D-Aspartate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde