Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1

J Neurosci. 2009 Jun 17;29(24):7857-68. doi: 10.1523/JNEUROSCI.1817-09.2009.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • 4,5,6,7-tetrachloroindan-1,3-dione
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • Indans
  • Indoles
  • Intracellular Signaling Peptides and Proteins
  • LDN 57444
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Mtap2 protein, mouse
  • Oximes
  • UCHL3 protein, mouse
  • Ubiquitin
  • Ubiquitin carboxyl-Terminal Hydrolase L-1, mouse
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • N-Methylaspartate
  • 2-Amino-5-phosphonovalerate
  • Guanylate Kinases
  • Ubiquitin Thiolesterase