The Ubiquitin Proteasome System Functions as an Inhibitory Constraint on Synaptic Strengthening

Zhao, Yali; Hegde, Ashok N.; Martin, Kelsey C.

doi:10.1016/s0960-9822(03)00332-4

Cited by 122 publications

(102 citation statements)

References 53 publications

(2 reference statements)

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“…Originally, it was found that proteasome inhibitors block the induction of LTF (Chain et al 1999). Later studies on LTF, however, showed that bath application of the active form of lactacystin, clasto-lactacystin b-lactone, to sensory-motor neuron synapses resulted in enhanced LTF and an increase in neurite outgrowth in isolated sensory neuron (Zhao et al 2003). The increase in neurite elongation is consistent with results obtained in PC12 and Neuro2A cells in which lactacystin induces neurite outgrowth (Fenteany et al 1994).…”

Section: Does the Proteasome Have Local Roles In Synaptic Plasticity?supporting

confidence: 72%

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The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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Section: Does the Proteasome Have Local Roles In Synaptic Plasticity?supporting

confidence: 72%

“…If the degradation of these proteins is prevented, then long-term memory formation becomes independent of transcription. In support of this idea, Zhao et al (2003) found that proteasome inhibitorinduced synaptic strengthening depends on translation but not transcription.…”

Section: Does the Proteasome Have Local Roles In Synaptic Plasticity?mentioning

confidence: 85%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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“…When degradation of an inhibitory protein is necessary for memory consolidation, proteasome inhibitors blocked the formation of longterm memory (Chain et al, 1999;Lopez-Salon et al, 2001;Upadhya et al, 2004). Conversely, when UPS functioned as an inhibitory constraint, removal of constraint by proteasome inhibitor enhanced synaptic transmission and facilitated memory formation (Zhao et al, 2003;Yeh et al, 2006). In the present study, we found that proteasome inhibitors blocked DCS-induced GluR1 internalization.…”

Section: Discussionsupporting

confidence: 53%

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

Mao

Lin

Gean

2008

Neuropsychopharmacol

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D-Cycloserine (DCS) has been shown to facilitate extinction of conditioned fear in rats and to improve fear reduction of social phobia and fear of heights in human studies. Here, we investigate the mechanism of DCS effect by measuring internalized GluR1 and GluR2 using cell-surface biotinylation techniques. DCS selectively increased NMDA receptor-mediated synaptic response without affecting AMPA receptor-mediated synaptic response. Low-frequency stimulation (LFS) when applied in the presence of DCS induced GluR1 and GluR2 internalization in the amygdala slices. Proteasome inhibitors block DCS facilitation of LFS-induced depotentiation and a reduction in surface levels of GluR1 and GluR2. Furthermore, DCS in combination with LFS reduced cellular levels of PSD-95 and synapse-associated protein 97 (SAP97), which were also blocked by proteasome inhibitors. In the in vivo experiments, DCS-induced reduction of fearpotentiated startle and reversal of conditioning-induced increase in surface expression of GluR1 were blocked by proteasome inhibitors. DCS-treated rats fail to exhibit reinstatement after US-alone presentations. These results suggest that DCS facilitates receptor internalization in the presence of extinction training, resulting in augmented reduction of startle potentiation.

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“…[F (3,31) = 4.38, P < 0.05, one-way ANOVA], *P < 0.05, **P < 0.01, Newman-Keuls multiple-comparison test. There was no significant difference among groups in the EPSP amplitudes of the first recording [F (3,31) system also functions as an inhibitory constraint on synaptic strength and growth in a translation-dependent, but not a transcription-dependent, manner (37). Indeed, consistent with results of Zhao et al (37), we also observed an increase of both basal synaptic transmission at sensory-to-motor neuron synapses in culture and reflex behavior in the presence of higher concentrations (1 μM) of βlac.…”

Section: Discussionmentioning

confidence: 94%

A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia

Lee

Kwak

Shim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill-and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, longterm facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval. memory reorganization | memory recall | 5-HT | local protein synthesis | clasto-lactacystin beta-lactone T he processes of memory reactivation (retrieval) have been the focus of several studies over the last decade. Retrieval is thought to return the memory to an unstable (labile) state, in which de novo protein synthesis-dependent reconsolidation is required to continue maintaining the memory over time (1-4). Memory reconsolidation has been reported for a variety of memory paradigms in a number of different animal models (1, 3, 5, 6); however, how memory reconsolidation works remains unclear.At least two nonmutually exclusive hypotheses have been proposed (7). One hypothesis suggests that reconsolidation is an updating process in which the synapses that encode the preexisting memory are reorganized after memory retrieval so as to recruit new synaptic connections that allow the incorporation of new information (8-10). The second hypothesis suggests a mechanism that is a continuation of the consolidation process at the same set of synaptic connections and that serves to strengthen memory, allowing it to become longer lasting and enduring and thereby preventing forgetting (11). Both of these views of reconsolidation are consistent with retraining or retrieval. In each case, synaptic reactivation could be implicit (e.g., during sleep) or explicit, and both would presumably have the same effect of making the memory stronger, more stable, and more resistant to postretrieval interference.Both types of reconsolidation hypotheses imply that the stored memory become...

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The Ubiquitin Proteasome System Functions as an Inhibitory Constraint on Synaptic Strengthening

Abstract: We conclude that both pre- and postsynaptic substrates of the ubiquitin proteasome function constitutively to regulate synaptic strength and growth and that the ubiquitin proteasome pathway functions in mature neurons as an inhibitory constraint on synaptic strengthening.

Cited by 122 publications

References 53 publications

The ubiquitin-proteasome pathway and synaptic plasticity

The ubiquitin-proteasome pathway and synaptic plasticity

Augmentation of Fear Extinction by D-Cycloserine is Blocked by Proteasome Inhibitors

A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia

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