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The Journal of Neuroscience, June 17, 2009, 29(24):7857-7868; doi:10.1523/JNEUROSCI.1817-09.2009

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Neurobiology of Disease
Regulation of Synaptic Structure by Ubiquitin C-Terminal Hydrolase L1

Anna E. Cartier,^1,2,3 Stevan N. Djakovic,¹ Afshin Salehi,¹ Scott M. Wilson,⁴ Eliezer Masliah,^2,3 and Gentry N. Patrick¹

¹Section of Neurobiology, Department of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0347, ²Departments of Neurosciences and ³Pathology, University of California, San Diego, La Jolla, California 92093-0624, and ⁴Department of Neurobiology, Civitan Research Center, University of Alabama, Birmingham, Alabama 35294

Correspondence should be addressed to Gentry N. Patrick at the above address. Email: gpatrick{at}ucsd.edu

Ubiquitin C-terminal hydrolase L1 (UCH-L1) is a deubiquitinating enzyme that is selectively and abundantly expressed in the brain, and its activity is required for normal synaptic function. Here, we show that UCH-L1 functions in maintaining normal synaptic structure in hippocampal neurons. We found that UCH-L1 activity is rapidly upregulated by NMDA receptor activation, which leads to an increase in the levels of free monomeric ubiquitin. Conversely, pharmacological inhibition of UCH-L1 significantly reduces monomeric ubiquitin levels and causes dramatic alterations in synaptic protein distribution and spine morphology. Inhibition of UCH-L1 activity increases spine size while decreasing spine density. Furthermore, there is a concomitant increase in the size of presynaptic and postsynaptic protein clusters. Interestingly, however, ectopic expression of ubiquitin restores normal synaptic structure in UCH-L1-inhibited neurons. These findings point to a significant role of UCH-L1 in synaptic remodeling, most likely by modulating free monomeric ubiquitin levels in an activity-dependent manner.

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Received April 15, 2009; revised May 14, 2009; accepted May 15, 2009.

Correspondence should be addressed to Gentry N. Patrick at the above address. Email: gpatrick{at}ucsd.edu

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