scholarly journals Altered phosphorylation of the proteasome subunit Rpt6 has minimal impact on synaptic plasticity and learning

2019 ◽  
Author(s):  
Samantha L. Scudder ◽  
Frankie R. Gonzales ◽  
Kristin K. Howell ◽  
Ivar S. Stein ◽  
Lara E. Dozier ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
26S Proteasome ◽  
Compensatory Mechanisms ◽  
Atpase Subunit ◽  
Minimal Impact ◽  
Proteasome Subunit ◽  
Aaa Atpase

ABSTRACTDynamic control of protein degradation via the ubiquitin proteasome system is thought to play a crucial role in neuronal function and synaptic plasticity. The proteasome subunit Rpt6, an AAA ATPase subunit of the 19S regulatory particle, has emerged as an important site for regulation of 26S proteasome function in neurons. Phosphorylation of Rpt6 on serine 120 (S120) can stimulate the catalytic rate of substrate degradation by the 26S proteasome and this site is targeted by the plasticity-related kinase calcium/calmodulin-dependent kinase II (CaMKII), making it an attractive candidate for regulation of proteasome function in neurons. Several in vitro studies have shown that altered Rpt6 S120 phosphorylation can affect the structure and function of synapses. To evaluate the importance of Rpt6 S120 phosphorylation in vivo, we created two mouse models which feature mutations at S120 that block or mimic phosphorylation at this site. We find that peptidase and ATPase activities are upregulated in the phospho-mimetic mutant and downregulated in the phospho-dead mutant (S120 mutated to aspartic acid (S120D) or alanine (S120A), respectively). Surprisingly, these mutations had no effect on basal synaptic transmission, long-term potentiation, and dendritic spine dynamics and density in the hippocampus. Furthermore, these mutants displayed no deficits in cued and contextual fear memory. Thus, in a mouse model that blocks or mimics phosphorylation at this site, either compensatory mechanisms negate these effects, or small variations in proteasome activity are not enough to induce significant changes in synaptic structure, plasticity, or behavior.

scholarly journals The proteasome cap RPT5/Rpt5p subunit prevents aggregation of unfolded ricin A chain

2013 ◽  
Vol 453 (3) ◽  
pp. 435-445 ◽  
Author(s):  
Paola Pietroni ◽  
Nishi Vasisht ◽  
Jonathan P. Cook ◽  
David M. Roberts ◽  
J. Michael Lord ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Proteasome Inhibitors ◽  
Retrograde Transport ◽  
26S Proteasome ◽  
Atpase Subunit ◽  
Aaa Atpase ◽  
A Chain ◽  
Ricin A

The plant cytotoxin ricin enters mammalian cells by receptor-mediated endocytosis, undergoing retrograde transport to the ER (endoplasmic reticulum) where its catalytic A chain (RTA) is reductively separated from the holotoxin to enter the cytosol and inactivate ribosomes. The currently accepted model is that the bulk of ER-dislocated RTA is degraded by proteasomes. We show in the present study that the proteasome has a more complex role in ricin intoxication than previously recognized, that the previously reported increase in sensitivity of mammalian cells to ricin in the presence of proteasome inhibitors simply reflects toxicity of the inhibitors themselves, and that RTA is a very poor substrate for proteasomal degradation. Denatured RTA and casein compete for a binding site on the regulatory particle of the 26S proteasome, but their fates differ. Casein is degraded, but the mammalian 26S proteasome AAA (ATPase associated with various cellular activities)-ATPase subunit RPT5 acts as a chaperone that prevents aggregation of denatured RTA and stimulates recovery of catalytic RTA activity in vitro. Furthermore, in vivo, the ATPase activity of Rpt5p is required for maximal toxicity of RTA dislocated from the Saccharomyces cerevisiae ER. The results of the present study implicate RPT5/Rpt5p in the triage of substrates in which either activation (folding) or inactivation (degradation) pathways may be initiated.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

scholarly journals Tyrosine phosphorylation of the AMPA receptor subunit GluA2 gates homeostatic synaptic plasticity

2020 ◽  
Vol 117 (9) ◽  
pp. 4948-4958 ◽  
Author(s):  
Adeline J. H. Yong ◽  
Han L. Tan ◽  
Qianwen Zhu ◽  
Alexei M. Bygrave ◽  
Richard C. Johnson ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Phosphorylation Site ◽  
Long Term Potentiation ◽  
Interacting Protein ◽  
Hebbian Plasticity ◽  
Term Potentiation ◽  
Ampa Receptor Subunit

Hebbian plasticity, comprised of long-term potentiation (LTP) and depression (LTD), allows neurons to encode and respond to specific stimuli; while homeostatic synaptic scaling is a counterbalancing mechanism that enables the maintenance of stable neural circuits. Both types of synaptic plasticity involve the control of postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) abundance, which is modulated by AMPAR phosphorylation. To address the necessity of GluA2 phospho-Y876 in synaptic plasticity, we generated phospho-deficient GluA2 Y876F knock-in mice. We show that, while GluA2 phospho-Y876 is not necessary for Hebbian plasticity, it is essential for both in vivo and in vitro homeostatic upscaling. Bidirectional changes in GluA2 phospho-Y876 were observed during homeostatic scaling, with a decrease during downscaling and an increase during upscaling. GluA2 phospho-Y876 is necessary for synaptic accumulation of glutamate receptor interacting protein 1 (GRIP1), a crucial scaffold protein that delivers AMPARs to synapses, during upscaling. Furthermore, increased phosphorylation at GluA2 Y876 increases GluA2 binding to GRIP1. These results demonstrate that AMPAR trafficking during homeostatic upscaling can be gated by a single phosphorylation site on the GluA2 subunit.

scholarly journals Photoactivatable CaMKII induces synaptic plasticity in single synapses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Akihiro C. E. Shibata ◽  
Hiromi H. Ueda ◽  
Kei Eto ◽  
Maki Onda ◽  
Aiko Sato ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Small Gtpase ◽  
Protein Activity ◽  
Photon Excitation ◽  
Term Potentiation ◽  
Neuronal Functions

AbstractOptogenetic approaches for studying neuronal functions have proven their utility in the neurosciences. However, optogenetic tools capable of inducing synaptic plasticity at the level of single synapses have been lacking. Here, we engineered a photoactivatable (pa)CaMKII by fusing a light-sensitive domain, LOV2, to CaMKIIα. Blue light or two-photon excitation reversibly activated paCaMKII. Activation in single spines was sufficient to induce structural long-term potentiation (sLTP) in vitro and in vivo. paCaMKII activation was also sufficient for the recruitment of AMPA receptors and functional LTP in single spines. By combining paCaMKII with protein activity imaging by 2-photon FLIM-FRET, we demonstrate that paCaMKII activation in clustered spines induces robust sLTP via a mechanism that involves the actin-regulatory small GTPase, Cdc42. This optogenetic tool for dissecting the function of CaMKII activation (i.e., the sufficiency of CaMKII rather than necessity) and for manipulating synaptic plasticity will find many applications in neuroscience and other fields.

scholarly journals Extensive phosphorylation of AMPA receptors in neurons

2016 ◽  
Vol 113 (33) ◽  
pp. E4920-E4927 ◽  
Author(s):  
Graham H. Diering ◽  
Seok Heo ◽  
Natasha K. Hussain ◽  
Bian Liu ◽  
Richard L. Huganir
Keyword(s):  
Synaptic Plasticity ◽  
Protein Interactions ◽  
Membrane Trafficking ◽  
Ampa Receptors ◽  
Posttranslational Modifications ◽  
Large Fraction ◽  
Large Body ◽  
Long Term Potentiation

Regulation of AMPA receptor (AMPAR) function is a fundamental mechanism controlling synaptic strength during long-term potentiation/depression and homeostatic scaling. AMPAR function and membrane trafficking is controlled by protein–protein interactions, as well as by posttranslational modifications. Phosphorylation of the GluA1 AMPAR subunit at S845 and S831 play especially important roles during synaptic plasticity. Recent controversy has emerged regarding the extent to which GluA1 phosphorylation may contribute to synaptic plasticity. Here we used a variety of methods to measure the population of phosphorylated GluA1-containing AMPARs in cultured primary neurons and mouse forebrain. Phosphorylated GluA1 represents large fractions from 12% to 50% of the total population under basal and stimulated conditions in vitro and in vivo. Furthermore, a large fraction of synapses are positive for phospho-GluA1–containing AMPARs. Our results support the large body of research indicating a prominent role of GluA1 phosphorylation in synaptic plasticity.

scholarly journals Lack of astrocytic glycogen alters synaptic plasticity but not seizure susceptibility

2020 ◽  
Author(s):  
Jordi Duran ◽  
M. Kathryn Brewer ◽  
Arnau Hervera ◽  
Agnès Gruart ◽  
Jose Antonio del Rio ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Long Term Potentiation ◽  
Electrophysiological Properties ◽  
Electrophysiological Recordings ◽  
Term Potentiation

ABSTRACTBrain glycogen is mainly stored in astrocytes. However, recent studies both in vitro and in vivo indicate that glycogen also plays important roles in neurons. By conditional deletion of glycogen synthase (GYS1), we previously developed a mouse model entirely devoid of glycogen in the central nervous system (GYS1Nestin-KO). These mice displayed altered electrophysiological properties in the hippocampus and increased susceptibility to kainate-induced seizures. To understand which of these functions is related to astrocytic glycogen, in the present study we generated a mouse model in which glycogen synthesis is eliminated specifically in astrocytes (GYS1Gfap-KO). Electrophysiological recordings of awake behaving mice revealed alterations in input/output curves and impaired long-term potentiation, similar, but to a lesser extent, to those obtained with GYS1Nestin-KO mice. Surprisingly, GYS1Gfap-KO mice displayed no change in susceptibility to kainate-induced seizures as determined by fEPSP recordings and video monitoring. These results confirm the importance of astrocytic glycogen in synaptic plasticity.

scholarly journals Phosphatase UBLCP1 controls proteasome assembly

Open Biology ◽  
2017 ◽  
Vol 7 (5) ◽  
pp. 170042 ◽  
Author(s):  
Shuangwu Sun ◽  
Sisi Liu ◽  
Zhengmao Zhang ◽  
Wang Zeng ◽  
Chuang Sun ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Essential Role ◽  
26S Proteasome ◽  
Core Particle ◽  
Proteasome Subunit ◽  
Bona Fide ◽  
Proteasome Regulation

Ubiquitin-like domain-containing C-terminal domain phosphatase 1 (UBLCP1), an FCP/SCP phosphatase family member, was identified as the first proteasome phosphatase. UBLCP1 binds to proteasome subunit Rpn1 and dephosphorylates the proteasome in vitro . However, it is still unclear which proteasome subunit(s) are the bona fide substrate(s) of UBLCP1 and the precise mechanism for proteasome regulation remains elusive. Here, we show that UBLCP1 selectively binds to the 19S regulatory particle (RP) through its interaction with Rpn1, but not the 20S core particle (CP) or the 26S proteasome holoenzyme. In the RP, UBLCP1 dephosphorylates the subunit Rpt1, impairs its ATPase activity, and consequently disrupts the 26S proteasome assembly, yet it has no effects on the RP assembly from precursor complexes. The Rpn1-binding and phosphatase activities of UBLCP1 are essential for its function on Rpt1 dephosphorylation and proteasome activity both in vivo and in vitro . Our study establishes the essential role of the UBLCP1/Rpn1/Rpt1 complex in regulating proteasome assembly.

scholarly journals Defective synapse maturation and enhanced synaptic plasticity in Shank2-/- mice

2017 ◽  
Author(s):  
Stephanie Wegener ◽  
Arne Buschler ◽  
A. Vanessa Stempel ◽  
Sarah A. Shoichet ◽  
Denise Manahan-Vaughan ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mechanistic Explanation ◽  
Long Term Potentiation ◽  
Autism Spectrum ◽  
Term Potentiation ◽  
Synapse Maturation ◽  
Spectrum Disorders

SummaryAutism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic aetiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are employed for a mechanistic understanding of ASDs and the development of therapeutic strategies. In sharp contrast to all studies so far on the function of SHANK proteins, we observe enhanced synaptic plasticity in Shank2-/- mice, under various conditions in vitro and in vivo. Reproducing and extending previous results, we here present a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation (LTP) by describing a synaptic maturation deficit in Shank2-/- mice.

scholarly journals Synaptic plasticity in animal models of early Alzheimer's disease

2003 ◽  
Vol 358 (1432) ◽  
pp. 821-828 ◽  
Author(s):  
Michael J. Rowan ◽  
Igor Klyubin ◽  
William K. Cullen ◽  
Roger Anwyl
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Active Species ◽  
Amyloid Β Protein ◽  
Early Alzheimer’S Disease

Amyloid β-protein (Aβ) is believed to be a primary cause of Alzheimer's disease (AD). Recent research has examined the potential importance of soluble species of Aβ in synaptic dysfunction, long before fibrillary Aβ is deposited and neurodegenerative changes occur. Hippocampal excitatory synaptic transmission and plasticity are disrupted in transgenic mice overexpressing human amyloid precursor protein with early onset familial AD mutations, and in rats after exogenous application of synthetic Aβ both in vitro and in vivo . Recently, naturally produced soluble Aβ was shown to block the persistence of long-term potentiation (LTP) in the intact hippocampus. Sub-nanomolar concentrations of oligomeric Aβ were sufficient to inhibit late LTP, pointing to a possible reason for the sensitivity of hippocampus-dependent memory to impairment in the early preclinical stages of AD. Having identified the active species of Aβ that can play havoc with synaptic plasticity, it is hoped that new ways of targeting early AD can be developed.

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats

2020 ◽  
Vol 17 (4) ◽  
pp. 354-360 ◽  
Author(s):  
Yu-Xing Ge ◽  
Ying-Ying Lin ◽  
Qian-Qian Bi ◽  
Yu-Juan Chen
Keyword(s):  
Synaptic Plasticity ◽  
Temporal Lobe Epilepsy ◽  
Synaptic Vesicle ◽  
Long Term Potentiation ◽  
Synaptic Dysfunction ◽  
Over Expression ◽  
Term Potentiation ◽  
Synaptic Vesicle Protein 2A

Background: Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. Objective: The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. Methods: The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. Results: An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. Conclusion: BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

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