A catalytic independent function of the deubiquitinating enzyme USP14 regulates hippocampal synaptic short-term plasticity and vesicle number

J Physiol. 2014 Feb 15;592(4):571-86. doi: 10.1113/jphysiol.2013.266015. Epub 2013 Nov 11.


The ubiquitin proteasome system is required for the rapid and precise control of protein abundance that is essential for synaptic function. USP14 is a proteasome-bound deubiquitinating enzyme that recycles ubiquitin and regulates synaptic short-term synaptic plasticity. We previously reported that loss of USP14 in ax(J) mice causes a deficit in paired pulse facilitation (PPF) at hippocampal synapses. Here we report that USP14 regulates synaptic function through a novel, deubiquitination-independent mechanism. Although PPF is usually inversely related to release probability, USP14 deficiency impairs PPF without altering basal release probability. Instead, the loss of USP14 causes a large reduction in the number of synaptic vesicles. Over-expression of a catalytically inactive form of USP14 rescues the PPF deficit and restores synaptic vesicle number, indicating that USP14 regulates presynaptic structure and function independently of its role in deubiquitination. Finally, the PPF deficit caused by loss of USP14 can be rescued by pharmacological inhibition of proteasome activity, suggesting that inappropriate protein degradation underlies the PPF impairment. Overall, we demonstrate a novel, deubiquitination-independent function for USP14 in influencing synaptic architecture and plasticity.

Publication types

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

MeSH terms

  • Animals
  • CA1 Region, Hippocampal / cytology
  • CA1 Region, Hippocampal / metabolism*
  • CA1 Region, Hippocampal / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Neuronal Plasticity*
  • Synapses / metabolism
  • Synapses / physiology
  • Synaptic Transmission
  • Synaptic Vesicles / metabolism*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination*


  • Usp14 protein, mouse
  • Ubiquitin Thiolesterase