Regulation of Synaptic Structure by Ubiquitin C-Terminal Hydrolase L1

• Published in: The Journal of neuroscience Vol. 29; no. 24; pp. 7857 - 7868
• Main Authors: Cartier, Anna E, Djakovic, Stevan N, Salehi, Afshin, Wilson, Scott M, Masliah, Eliezer, Patrick, Gentry N
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 17-06-2009; Society for Neuroscience
• Subjects: 2-Amino-5-phosphonovalerate - pharmacology; Animals; Animals, Newborn; Cells, Cultured; Dendrites - metabolism; Dendrites - ultrastructure; Disks Large Homolog 4 Protein; Enzyme Inhibitors - pharmacology; Excitatory Amino Acid Agents - pharmacology; Gene Expression Regulation - drug effects; Gene Expression Regulation - genetics; Green Fluorescent Proteins - genetics; Guanylate Kinases; Hippocampus - cytology; Humans; Indans - pharmacology; Indoles - pharmacology; Intracellular Signaling Peptides and Proteins - metabolism; Membrane Proteins - metabolism; Mice; Mice, Knockout; Microscopy, Electron, Transmission - methods; Microtubule-Associated Proteins - metabolism; N-Methylaspartate; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Oximes - pharmacology; Subcellular Fractions - metabolism; Subcellular Fractions - ultrastructure; Synapses - drug effects; Synapses - metabolism; Synapses - physiology; Synapses - ultrastructure; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Transfection; Ubiquitin - genetics; Ubiquitin - metabolism; Ubiquitin Thiolesterase - antagonists & inhibitors; Ubiquitin Thiolesterase - deficiency; Ubiquitin Thiolesterase - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.1817-09.2009

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.