scholarly journals Enhancement of synaptic AMPA receptors depends mutually on Src and PSD-95

2020 ◽  
Author(s):  
Xiaojie Huang ◽  
Juliane M. Krüger ◽  
Anna Beroun ◽  
Weifeng Xu ◽  
Yan Dong ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Ampa Receptors ◽  
Domain Swapping ◽  
Mutual Dependence ◽  
Protein Motifs ◽  
Signaling Mechanisms ◽  
Continuous Activity ◽  
Maguk Protein

AbstractSynaptic incorporation and removal of AMPA receptors is highly regulated to modulate the strength of synaptic transmission for long-term synaptic plasticity during brain development and associative learning. PSD-93α2 and PSD-95α, two paralogs of the DLG-MAGUK protein family of signaling scaffolds govern the synaptic incorporation and stabilization of AMPA receptors opposingly, with PSD-95α promoting and PSD-93α2 inhibiting it. The associated signaling mechanisms that control the synaptic incorporation and stabilization remain elusive. Here, we used domain swapping between the antagonizing signaling scaffolds to identify the protein motifs responsible for enhancing synaptic AMPA receptors and the associated signaling protein. We narrowed down multiple motifs in the N-terminal domain that are principally responsible for governing the enhancement by Src. Specific activation and inhibiting peptides revealed continuous activity of Src. Together, the results depict a mutual dependence of Src and PSD-95α in enhancing and maintaining synaptic AMPA receptors.

scholarly journals GluR2 protein-protein interactions and the regulation of AMPA receptors during synaptic plasticity

2003 ◽  
Vol 358 (1432) ◽  
pp. 715-720 ◽  
Author(s):  
Fabrice Duprat ◽  
Michael Daw ◽  
Wonil Lim ◽  
Graham Collingridge ◽  
John Isaac
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Protein Interactions ◽  
Ampa Receptors ◽  
Long Term Potentiation ◽  
Synaptic Proteins ◽  
Mammalian Brain ◽  
Protein Protein Interactions ◽  
Term Potentiation

AMPA-type glutamate receptors mediate most fast excitatory synaptic transmissions in the mammalian brain. They are critically involved in the expression of long-term potentiation and long-term depression, forms of synaptic plasticity that are thought to underlie learning and memory. A number of synaptic proteins have been identified that interact with the intracellular C-termini of AMPA receptor subunits. Here, we review recent studies and present new experimental data on the roles of these interacting proteins in regulating the AMPA receptor function during basal synaptic transmission and plasticity.

scholarly journals Binding of Filamentous Actin to CaMKII as a Potential Mechanism for the Regulation of Bidirectional Synaptic Plasticity by βCaMKII in Cerebellar Purkinje Cells

2019 ◽  
Author(s):  
Thiago M. Pinto ◽  
Maria J. Schilstra ◽  
Antonio C. Roque ◽  
Volker Steuber
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Filamentous Actin ◽  
Parallel Fibre ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Protein Phosphatase 2B ◽  
Dependent Protein ◽  
Cerebellar Purkinje Cells

AbstractCalcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the β isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how βCaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that βCaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the β isoform of the kinase to regulate bidirectional plasticity at these synapses.Author SummaryMany molecules and the complex interactions between them are involved in synaptic plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) is an important component of the signalling network that is responsible for plasticity in cerebellar Purkinje cells (PCs). The CaMKII holoenzyme contains different isoforms such as αCaMKII and βCaMKII. Experiments with Camk2b knockout mice that lack the β isoform of CaMKII demonstrated that βCaMKII regulates the direction of plasticity at parallel fibre (PF)-PC synapses. Stimulation protocols that induce long-term depression in wild-type mice, which contain both α and βCaMKII, lead to long-term potentiation in knockout mice without βCaMKII, and vice versa. We developed a kinetic simulation of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B to investigate how βCaMKII can control bidirectional synaptic plasticity in cerebellar PCs. Our simulation results demonstrate that the binding of filamentous actin to βCaMKII can contribute to the regulation of bidirectional plasticity at PF-PC synapses. Our computational model of intracellular signalling significantly advances the understanding of the mechanisms of synaptic plasticity induction in the cerebellum.

scholarly journals Species-specific differences in synaptic transmission and plasticity

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Prateep Beed ◽  
Saikat Ray ◽  
Laura Moreno Velasquez ◽  
Alexander Stumpf ◽  
Daniel Parthier ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Mossy Fiber ◽  
Mossy Fibers ◽  
Evolutionary Divergence ◽  
Short Term Plasticity ◽  
Species Specific ◽  
The Brain ◽  
Lower Expression

Abstract Synaptic transmission and plasticity in the hippocampus are integral factors in learning and memory. While there has been intense investigation of these critical mechanisms in the brain of rodents, we lack a broader understanding of the generality of these processes across species. We investigated one of the smallest animals with conserved hippocampal macroanatomy—the Etruscan shrew, and found that while synaptic properties and plasticity in CA1 Schaffer collateral synapses were similar to mice, CA3 mossy fiber synapses showed striking differences in synaptic plasticity between shrews and mice. Shrew mossy fibers have lower long term plasticity compared to mice. Short term plasticity and the expression of a key protein involved in it, synaptotagmin 7 were also markedly lower at the mossy fibers in shrews than in mice. We also observed similar lower expression of synaptotagmin 7 in the mossy fibers of bats that are evolutionarily closer to shrews than mice. Species specific differences in synaptic plasticity and the key molecules regulating it, highlight the evolutionary divergence of neuronal circuit functions.

scholarly journals Signaling Mechanisms Mediating BDNF Modulation of Synaptic Plasticity in the Hippocampus

1999 ◽  
Vol 6 (3) ◽  
pp. 243-256 ◽  
Author(s):  
Wolfram A. Gottschalk ◽  
Hao Jiang ◽  
Nicole Tartaglia ◽  
Linyin Feng ◽  
Alexander Figurov ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Neurotrophic Factor ◽  
High Frequency ◽  
Hippocampal Slices ◽  
Close Relative ◽  
Signaling Mechanisms ◽  
Neurotrophin 3 ◽  
Neurotrophin Signaling

Although recent studies indicate that brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity, the underlying signaling mechanisms remain largely unknown. Here, we have characterized the signaling events that mediate the BDNF modulation of high-frequency synaptic transmission. Mitogen-associated protein kinase (MAPK), phosphotidylinositol-3 kinase (PI3K), and phospholipase C-γ (PLC-γ) are the three signaling pathways known to mediate neurotrophin signaling in other systems. In neonatal hippocampal slices, application of BDNF rapidly activated MAPK and PI3K but not PLC-γ. BDNF greatly attenuated synaptic fatigue at CA1 synapses induced by a train of high-frequency, tetanic stimulation (HFS). Inhibition of the MAPK and PI3K, but not PLC-γ, prevented the BDNF modulation of high-frequency synaptic transmission. Neurotrophin-3 (NT-3), a close relative of BDNF, did not activate MAPK or PI3K and had no effect on synaptic fatigue in the neonatal hippocampus. Neither forskolin, which activated MAPK but not PI3 kinase, nor ciliary neurotrophic factor (CNTF), which activated PI3K but not MAPK, affected HFS-induced synaptic fatigue. Treatment of the slices with forskolin together with CNTF still had no effect on synaptic fatigue. Thus, although the activation of MAPK and PI3K is required, the two together are not sufficient to mediate the BDNF effect. Inhibition of new protein synthesis by anisomycin or cycloheximide did not prevent the BDNF effect. These data suggest that BDNF modulation of high-frequency transmission is independent of protein synthesis but requires MAPK and PI3K and yet another signaling pathway to act together in the hippocampus.

scholarly journals Modulation of AMPA Receptors by Nitric Oxide in Nerve Cells

2020 ◽  
Vol 21 (3) ◽  
pp. 981 ◽  
Author(s):  
Violetta O. Ivanova ◽  
Pavel M. Balaban ◽  
Natalia V. Bal
Keyword(s):  
Nitric Oxide ◽  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Surface Expression ◽  
Gaseous Molecule ◽  
Main Target ◽  
Nmda Glutamate Receptors ◽  
Synaptic Changes ◽  
The Brain

Nitric oxide (NO) is a gaseous molecule with a large number of functions in living tissue. In the brain, NO participates in numerous intracellular mechanisms, including synaptic plasticity and cell homeostasis. NO elicits synaptic changes both through various multi-chain cascades and through direct nitrosylation of targeted proteins. Along with the N-methyl-d-aspartate (NMDA) glutamate receptors, one of the key components in synaptic functioning are α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors—the main target for long-term modifications of synaptic effectivity. AMPA receptors have been shown to participate in most of the functions important for neuronal activity, including memory formation. Interactions of NO and AMPA receptors were observed in important phenomena, such as glutamatergic excitotoxicity in retinal cells, synaptic plasticity, and neuropathologies. This review focuses on existing findings that concern pathways by which NO interacts with AMPA receptors, influences properties of different subunits of AMPA receptors, and regulates the receptors’ surface expression.

Regulation of hippocampal information encoding by metabotopic glutamate receptors

Neuroforum ◽  
2018 ◽  
Vol 24 (3) ◽  
pp. A121-A126
Author(s):  
Denise Manahan-Vaughan
Keyword(s):  
Synaptic Plasticity ◽  
Glutamate Receptors ◽  
Ampa Receptors ◽  
Receptor Activation ◽  
Information Storage ◽  
Long Term Memory ◽  
Information Encoding ◽  
Metabotropic Glutamate ◽  
Long Term Storage

Abstract The hippocampus supports the acquisition of both spatial representations and long-term spatial memory. This is enabled by a triumvirate of physiological processes comprising information organisation and transfer by means of neuronal oscillations, creation of context-dependent spatial maps by means of place cells, and long-term storage of spatial experience by means of synaptic plasticity. All three processes are enabled by the glutamatergic system. Glutamate binding to ionotropic glutamate receptors enables both fast excitatory synaptic transmission (via AMPA receptors) and the initiation of long-term synaptic storage (via NMDA receptors). But glutamate also binds to metabotropic glutamate (mGlu) receptors. These receptors not only contribute to the stability of hippocampal encoding and the longevity of synaptic plasticity, they can also support synaptic information storage independent of NMDA receptor activation and are important for the acquisition and retention of long-term memory.

scholarly journals CAP2 is a novel regulator of Cofilin in synaptic plasticity and Alzheimer’s disease

2019 ◽  
Author(s):  
Silvia Pelucchi ◽  
Lina Vandermeulen ◽  
Lara Pizzamiglio ◽  
Bahar Aksan ◽  
Jing Yan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Long Term Potentiation ◽  
Actin Dynamics ◽  
Term Potentiation ◽  
Actin Turnover ◽  
Normal Spine

AbstractCofilin is one of the major regulators of actin dynamics in spines where it is required for structural synaptic plasticity. However, our knowledge of the mechanisms controlling Cofilin activity in spines remains still fragmented. Here, we describe the cyclase-associated protein 2 (CAP2) as a novel master regulator of Cofilin localization in spines. The formation of CAP2 dimers through its Cys32 is important for CAP2 binding to Cofilin and for normal spine actin turnover. The Cys32-dependent CAP2 homodimerization and association to Cofilin are triggered by long-term potentiation (LTP) and are required for LTP-induced Cofilin translocation into spines, spine remodeling and the potentiation of synaptic transmission. This mechanism is specifically affected in the hippocampus, but not in the superior frontal gyrus, of both Alzheimer’s Disease (AD) patients and APP/PS1 mice, where CAP2 is down-regulated and CAP2 dimer synaptic levels are reduced. In AD hippocampi, Cofilin preferentially associates with CAP2 monomer and is aberrantly localized in spines. Taken together, these results provide novel insights into structural plasticity mechanisms that are defective in AD.

scholarly journals SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

2019 ◽  
Author(s):  
I. González-Calvo ◽  
K. Iyer ◽  
M. Carquin ◽  
A. Khayachi ◽  
F.A. Giuliani ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Ubiquitin Ligases ◽  
Potential Contribution ◽  
Dependent Manner ◽  
Activity Dependent

SummaryAt excitatory synapses, the choice between recycling or degradation of glutamate AMPA receptors controls the direction of synaptic plasticity. In this context, how the degradation machinery is targeted to specific synaptic substrates in an activity-dependent manner is not understood. Here we show that SUSD4, a complement-related transmembrane protein, is a tether for HECT ubiquitin ligases of the NEDD4 subfamily, which promote the degradation of a large number of cellular substrates. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function of Susd4 in the mouse prevents activity-dependent degradation of the GLUA2 AMPA receptor subunit and long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. SUSD4 could thus act as an adaptor targeting NEDD4 ubiquitin ligases to AMPA receptors during long-term synaptic plasticity. These findings shed light on the potential contribution of SUSD4 mutations to the etiology of neurodevelopmental diseases.

scholarly journals Binding of Filamentous Actin to CaMKII as a Potential Mechanism for the Regulation of Bidirectional Synaptic Plasticity by βCaMKII in Cerebellar Purkinje Cells

2019 ◽  
Author(s):  
Thiago M. Pinto ◽  
Maria J. Schilstra ◽  
Antonio C. Roque ◽  
Volker Steuber
Keyword(s):  
Synaptic Plasticity ◽  
Ampa Receptors ◽  
Filamentous Actin ◽  
Parallel Fibre ◽  
Dependent Protein Kinase ◽  
Calcium Calmodulin Dependent ◽  
Protein Phosphatase 2B ◽  
Dependent Protein ◽  
Cerebellar Purkinje Cells

AbstractCalcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but little is known about its functional role during plasticity induction in the cerebellum. Experiments have indicated that the β isoform of CaMKII controls the bidirectional inversion of plasticity at parallel fibre (PF)-Purkinje cell (PC) synapses in cerebellar cortex. Because the cellular events that underlie these experimental findings are still poorly understood, we developed a simple computational model to investigate how βCaMKII regulates the direction of plasticity in cerebellar PCs. We present the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. Our simulation results suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors can determine whether LTD or LTP occurs in cerebellar PCs. The model replicates experimental observations that indicate that βCaMKII controls the direction of plasticity at PF-PC synapses, and demonstrates that the binding of filamentous actin to CaMKII can enable the β isoform of the kinase to regulate bidirectional plasticity at these synapses.Author SummaryMany molecules and the complex interactions between them are involved in synaptic plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) is an important component of the signalling network that is responsible for plasticity in cerebellar Purkinje cells (PCs). The CaMKII holoenzyme contains different isoforms such as αCaMKII and βCaMKII. Experiments with Camk2b knockout mice that lack the β isoform of CaMKII demonstrated that βCaMKII regulates the direction of plasticity at parallel fibre (PF)-PC synapses. Stimulation protocols that induce long-term depression in wild-type mice, which contain both α and βCaMKII, lead to long-term potentiation in knockout mice without βCaMKII, and vice versa. We developed a kinetic simulation of the phosphorylation and dephosphorylation of AMPA receptors by CaMKII and protein phosphatase 2B to investigate how βCaMKII can control bidirectional synaptic plasticity in cerebellar PCs. Our simulation results demonstrate that the binding of filamentous actin to βCaMKII can contribute to the regulation of bidirectional plasticity at PF-PC synapses. Our computational model of intracellular signalling significantly advances the understanding of the mechanisms of synaptic plasticity induction in the cerebellum.

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