PMID- 29407217 OWN - NLM STAT- MEDLINE DCOM- 20181105 LR - 20181105 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 133 DP - 2018 May 1 TI - The role of 19S proteasome associated deubiquitinases in activity-dependent hippocampal synaptic plasticity. PG - 354-365 LID - S0028-3908(18)30049-2 [pii] LID - 10.1016/j.neuropharm.2018.01.043 [doi] AB - Posttranslational modification and degradation of proteins by the ubiquitin-proteasome system (UPS) is crucial to synaptic transmission. It is well established that 19S proteasome associated deubiquitinases (DUBs) reverse the process of ubiquitination by removing ubiquitin from their substrates. However, their potential contribution to hippocampal synaptic plasticity has not been addressed in detail. Here, we report that inhibition of the 19S proteasome associated DUBs, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14) by b-AP15 results in an accumulation of polyubiquitinated proteins and a reduction of monomeric ubiquitin without overt effects on 26S proteasome activity. b-AP15 led to a suppression of mTOR-p70S6K signaling and an increase in levels of p-p38 MAPK, two pathways essentially involved in establishing various forms of activity-dependent plasticity. Additionally, b-AP15 impaired the induction of late-phase long-term potentiation (L-LTP), induced the transformation of mGluR-mediated protein synthesis-independent long-term depression (early-LTD) to L-LTD and promoted heterosynaptic stabilization through synaptic tagging/capture (STC) in the hippocampal CA1 region of mice. The activity of 19S proteasome associated DUBs was also required for the enhancement of short-term potentiation (STP) induced by brain-derived neurotrophic factor (BDNF). Altogether, these results indicate an essential role of 19S proteasome associated DUBs in regulating activity-dependent hippocampal synaptic plasticity. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Yun, Di AU - Yun D AD - Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China. FAU - Zhuang, Yinghan AU - Zhuang Y AD - Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China. FAU - Kreutz, Michael R AU - Kreutz MR AD - Research Group Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany; Leibniz Group "Dendritic Organelles and Synaptic Function", Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. FAU - Behnisch, Thomas AU - Behnisch T AD - Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China. Electronic address: behnish@fudan.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180131 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Piperidones) RN - 0 (Protease Inhibitors) RN - 0 (Ubiquitin) RN - EC 3.4.19.12 (Deubiquitinating Enzymes) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cell Line, Transformed MH - Deubiquitinating Enzymes/*metabolism MH - Electric Stimulation MH - Excitatory Postsynaptic Potentials/drug effects/physiology MH - Hippocampus/*cytology MH - In Vitro Techniques MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Neuronal Plasticity/drug effects/*physiology MH - Patch-Clamp Techniques MH - Piperidones/pharmacology MH - Protease Inhibitors/pharmacology MH - Proteasome Endopeptidase Complex/*metabolism MH - Transfection MH - Ubiquitin/*metabolism MH - Ubiquitination/drug effects OTO - NOTNLM OT - 19S proteasome OT - BDNF OT - Deubiquitinases OT - Synaptic plasticity OT - Synaptic tagging EDAT- 2018/02/07 06:00 MHDA- 2018/11/06 06:00 CRDT- 2018/02/07 06:00 PHST- 2017/08/18 00:00 [received] PHST- 2017/12/24 00:00 [revised] PHST- 2018/01/29 00:00 [accepted] PHST- 2018/02/07 06:00 [pubmed] PHST- 2018/11/06 06:00 [medline] PHST- 2018/02/07 06:00 [entrez] AID - S0028-3908(18)30049-2 [pii] AID - 10.1016/j.neuropharm.2018.01.043 [doi] PST - ppublish SO - Neuropharmacology. 2018 May 1;133:354-365. doi: 10.1016/j.neuropharm.2018.01.043. Epub 2018 Jan 31.