20 results on '"Cezar M. Tigaret"'
Search Results
2. Neuromodulation of the feedforward dentate gyrus-CA3 microcircuit
- Author
-
Luke Yuri Prince, Travis J Bacon, Cezar M. Tigaret, and Jack R Mellor
- Subjects
Acetylcholine ,CA3 Region, Hippocampal ,Dentate Gyrus ,Dopamine ,Mossy Fibers, Hippocampal ,Serotonin ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
The feedforward dentate gyrus-CA3 microcircuit in the hippocampus is thought to activate ensembles of CA3 pyramidal cells and interneurons to encode and retrieve episodic memories. The creation of these CA3 ensembles depends on neuromodulatory input and synaptic plasticity within this microcircuit. Here we review the mechanisms by which the neuromodulators aceylcholine, noradrenaline, dopamine, and serotonin reconfigure this microcircuit and thereby infer the net effect of these modulators on the processes of episodic memory encoding and retrieval.
- Published
- 2016
- Full Text
- View/download PDF
3. Nuclear ERK1/2 signaling potentiation enhances neuroprotection and cognition via Importinα1/KPNA2
- Author
-
Marzia Indrigo, Ilaria Morella, Daniel Orellana, Raffaele d'Isa, Alessandro Papale, Riccardo Parra, Antonia Gurgone, Daniela Lecca, Anna Cavaccini, Cezar M Tigaret, Alfredo Cagnotto, Kimberley Jones, Simon Brooks, Gian Michele Ratto, Nicholas D Allen, Mariah J Lelos, Silvia Middei, Maurizio Giustetto, Anna R Carta, Raffaella Tonini, Mario Salmona, Jeremy Hall, Kerrie Thomas, Riccardo Brambilla, and Stefania Fasano
- Subjects
cell penetrating peptide therapeutics ,cognitive enhancement ,ERK signaling ,KPNA2 ,neuroprotection ,Medicine (General) ,R5-920 ,Genetics ,QH426-470 - Abstract
Abstract Cell signaling is central to neuronal activity and its dysregulation may lead to neurodegeneration and cognitive decline. Here, we show that selective genetic potentiation of neuronal ERK signaling prevents cell death in vitro and in vivo in the mouse brain, while attenuation of ERK signaling does the opposite. This neuroprotective effect mediated by an enhanced nuclear ERK activity can also be induced by the novel cell penetrating peptide RB5. In vitro administration of RB5 disrupts the preferential interaction of ERK1 MAP kinase with importinα1/KPNA2 over ERK2, facilitates ERK1/2 nuclear translocation, and enhances global ERK activity. Importantly, RB5 treatment in vivo promotes neuroprotection in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) disease, and enhances ERK signaling in a human cellular model of HD. Additionally, RB5‐mediated potentiation of ERK nuclear signaling facilitates synaptic plasticity, enhances cognition in healthy rodents, and rescues cognitive impairments in AD and HD models. The reported molecular mechanism shared across multiple neurodegenerative disorders reveals a potential new therapeutic target approach based on the modulation of KPNA2‐ERK1/2 interactions.
- Published
- 2023
- Full Text
- View/download PDF
4. A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics
- Author
-
Yuri Elias Rodrigues, Cezar M Tigaret, Hélène Marie, Cian O'Donnell, and Romain Veltz
- Subjects
synaptic plasticity ,computational neurosciences ,hippocampus ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Discovering the rules of synaptic plasticity is an important step for understanding brain learning. Existing plasticity models are either (1) top-down and interpretable, but not flexible enough to account for experimental data, or (2) bottom-up and biologically realistic, but too intricate to interpret and hard to fit to data. To avoid the shortcomings of these approaches, we present a new plasticity rule based on a geometrical readout mechanism that flexibly maps synaptic enzyme dynamics to predict plasticity outcomes. We apply this readout to a multi-timescale model of hippocampal synaptic plasticity induction that includes electrical dynamics, calcium, CaMKII and calcineurin, and accurate representation of intrinsic noise sources. Using a single set of model parameters, we demonstrate the robustness of this plasticity rule by reproducing nine published ex vivo experiments covering various spike-timing and frequency-dependent plasticity induction protocols, animal ages, and experimental conditions. Our model also predicts that in vivo-like spike timing irregularity strongly shapes plasticity outcome. This geometrical readout modelling approach can be readily applied to other excitatory or inhibitory synapses to discover their synaptic plasticity rules.
- Published
- 2023
- Full Text
- View/download PDF
5. A stochastic model of hippocampal synaptic plasticity with geometrical readout of enzyme dynamics
- Author
-
Yuri Elias Rodrigues, Cian O'Donnell, Hélène Marie, Romain Veltz, Cezar M. Tigaret, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Cardiff University, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), University of the West of England [Bristol] (UWE Bristol), Institut National de Recherche en Informatique et en Automatique (Inria), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
- Subjects
0303 health sciences ,Quantitative Biology::Neurons and Cognition ,Stochastic modelling ,Computer science ,Mechanism (biology) ,Robustness (evolution) ,Rule-based system ,Plasticity ,03 medical and health sciences ,0302 clinical medicine ,Synaptic plasticity ,Excitatory postsynaptic potential ,Representation (mathematics) ,Biological system ,030217 neurology & neurosurgery ,[MATH.MATH-NA]Mathematics [math]/Numerical Analysis [math.NA] ,030304 developmental biology - Abstract
Discovering the rules of synaptic plasticity is an important step for understanding brain learning. Existing plasticity models are either 1) top-down and interpretable, but not flexible enough to account for experimental data, or 2) bottom-up and biologically realistic, but too intricate to interpret and hard to fit to data. To avoid the shortcomings of these approaches, we present a new plasticity rule based on a geometrical readout mechanism that flexibly maps synaptic enzyme dynamics to predict plasticity outcomes. We apply this readout to a multi-timescale model of hippocampal synaptic plasticity induction that includes electrical dynamics, calcium, CaMKII and calcineurin, and accurate representation of intrinsic noise sources. Using a single set of model parameters, we demonstrate the robustness of this plasticity rule by reproducing nine publishedex vivoexperiments covering various spike-timing and frequency-dependent plasticity induction protocols, animal ages, and experimental conditions. Our model also predicts thatin vivo-like spike timing irregularity strongly shapes plasticity outcome. This geometrical readout modelling approach can be readily applied to other excitatory or inhibitory synapses to discover their synaptic plasticity rules.
- Published
- 2021
6. Neurotrophin receptor activation rescues cognitive and synaptic abnormalities caused by mutation of the psychiatric risk gene Cacna1c
- Author
-
Michael John Owen, Michael Conlon O'Donovan, Edward R. Morrell, Lucy Sykes, Tzu-Ching E. Lin, Kerrie L. Thomas, Lawrence Stephen Wilkinson, Cezar M. Tigaret, Jeremy Hall, and Matt Jones
- Subjects
medicine.medical_specialty ,Psychosis ,Dendritic spine ,biology ,Tropomyosin receptor kinase B ,medicine.disease ,Tropomyosin receptor kinase C ,Schizophrenia ,Synaptic plasticity ,medicine ,biology.protein ,Synaptic signaling ,Psychiatry ,Neurotrophin - Abstract
Genetic variation in CACNA1C, which encodes the alpha-1 subunit of CaV1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia and bipolar disorder. To translate genetics to neurobiological mechanisms and rational therapeutic targets, we investigated the impact of altered Cacna1c dosage on rat cognitive, synaptic and circuit phenotypes implicated by patient studies. We show that rats hemizygous for Cacna1c harbor marked impairments in learning to disregard non-salient stimuli, a behavioral change previously associated with psychosis. This behavioral deficit is accompanied by dys-coordinated network oscillations during learning, pathway-selective disruption of hippocampal synaptic plasticity, attenuated Ca2+ signaling in dendritic spines and decreased signaling through the Extracellular-signal Regulated Kinase (ERK) pathway. Activation of the ERK pathway by a small molecule agonist of TrkB/TrkC neurotrophin receptors rescued both behavioral and synaptic plasticity deficits in Cacna1c+/- rats. These results map a route through which genetic variation in CACNA1C can disrupt experience-dependent synaptic signaling and circuit activity, culminating in cognitive alterations associated with psychiatric disorders. Our findings highlight targeted activation of neurotrophin signaling pathways with BDNF mimetic drugs as a novel, genetically informed therapeutic approach for rescuing behavioral abnormalities in psychiatric disorder.One Sentence SummaryNeurotrophin receptor activation reveals that BDNF mimetic drugs have therapeutic potential to ameliorate genetic risk for psychiatric disorders.
- Published
- 2020
7. Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus
- Author
-
Jeremy Hall, Cezar M. Tigaret, Sophie E.L. Chamberlain, Michael C. Ashby, Joseph H.L.P. Sadowski, and Jack R. Mellor
- Subjects
Male ,0301 basic medicine ,Small-Conductance Calcium-Activated Potassium Channels ,hippocampus ,metabotropic glutamate receptors ,SK channel ,03 medical and health sciences ,Organ Culture Techniques ,0302 clinical medicine ,Excitatory Amino Acid Agonists ,medicine ,LTP induction ,Animals ,Rats, Wistar ,Research Articles ,Neuronal Plasticity ,muscarinic receptors ,synaptic plasticity ,Chemistry ,musculoskeletal, neural, and ocular physiology ,General Neuroscience ,Receptor, Muscarinic M1 ,Excitatory Postsynaptic Potentials ,spike timing-dependent plasticity ,Long-term potentiation ,Rats ,Microscopy, Fluorescence, Multiphoton ,030104 developmental biology ,medicine.anatomical_structure ,Apamin ,nervous system ,Schaffer collateral ,Metabotropic glutamate receptor ,Synaptic plasticity ,NMDA receptor ,Metabotropic glutamate receptor 1 ,SK channels ,Neuroscience ,030217 neurology & neurosurgery ,Cellular/Molecular ,Signal Transduction - Abstract
Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits.SIGNIFICANCE STATEMENTMemory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.
- Published
- 2018
8. Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders
- Author
-
Stefania Fasano, Anna Cavaccini, Daniela Lecca, Maurizio Giustetto, Raffaella Tonini, Silvia Middei, Riccardo Parra, Alessandro Papale, Cezar M. Tigaret, Riccardo Brambilla, Jeremy Hall, Simon Philip Brooks, Ilaria Morella, Gian Michele Ratto, Daniel Orellana, Anna R. Carta, Marzia Indrigo, Antonia Gurgone, Raffaele d’Isa, and Kerrie L. Thomas
- Subjects
MAPK/ERK pathway ,Cell signaling ,Programmed cell death ,Synaptic plasticity ,Neurodegeneration ,medicine ,Long-term potentiation ,Biology ,Cognitive decline ,medicine.disease ,Neuroscience ,Neuroprotection - Abstract
Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntington's (HD), Alzheimer's (AD), and Parkinson's disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.
- Published
- 2018
- Full Text
- View/download PDF
9. Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization
- Author
-
Barbara Imperiali, Kevin Thiolon, Christelle Breillat, Nelson B. Olivier, Christel Poujol, Lucie Bard, Matthieu Sainlos, Daniel Choquet, and Cezar M. Tigaret
- Subjects
Models, Molecular ,Scaffold protein ,Guanylate kinase ,PDZ domain ,AMPA receptor ,Ligands ,Divalent ,03 medical and health sciences ,0302 clinical medicine ,Biomimetics ,Receptors, AMPA ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,musculoskeletal, neural, and ocular physiology ,Cell Biology ,Transmembrane protein ,nervous system ,chemistry ,Biochemistry ,Structural biology ,Synapses ,Biophysics ,Ligand-gated ion channel ,030217 neurology & neurosurgery - Abstract
The interactions of the AMPA receptor (AMPAR) auxiliary subunit Stargazin with PDZ domain-containing scaffold proteins such as PSD-95 are critical for the synaptic stabilization of AMPARs. To investigate these interactions, we have developed biomimetic competing ligands that are assembled from two Stargazin-derived PSD-95/DLG/ZO-1 (PDZ) domain-binding motifs using 'click' chemistry. Characterization of the ligands in vitro and in a cellular FRET-based model revealed an enhanced affinity for the multiple PDZ domains of PSD-95 compared to monovalent peptides. In cultured neurons, the divalent ligands competed with transmembrane AMPAR regulatory protein (TARP) for the intracellular membrane-associated guanylate kinase resulting in increased lateral diffusion and endocytosis of surface AMPARs, while showing strong inhibition of synaptic AMPAR currents. This provides evidence for a model in which the TARP-containing AMPARs are stabilized at the synapse by engaging in multivalent interactions. In light of the prevalence of PDZ domain clusters, these new biomimetic chemical tools could find broad application for acutely perturbing multivalent complexes.
- Published
- 2010
10. Clathrin-independent trafficking of AMPA receptors
- Author
-
Oleg O, Glebov, Cezar M, Tigaret, Jack R, Mellor, and Jeremy M, Henley
- Subjects
Dynamins ,Male ,Neurons ,rac1 GTP-Binding Protein ,musculoskeletal, neural, and ocular physiology ,Long-Term Synaptic Depression ,Cell Culture Techniques ,Hydrazones ,Hippocampus ,Actins ,Clathrin ,Rats ,Protein Transport ,Pyrimidines ,nervous system ,Aminoquinolines ,Animals ,Receptors, AMPA ,RNA, Small Interfering ,Brief Communications - Abstract
Membrane trafficking of AMPA receptors (AMPARs) is critical for neuronal function and plasticity. Although rapid forms of AMPAR internalization during long-term depression (LTD) require clathrin and dynamin, the mechanisms governing constitutive AMPAR turnover and internalization of AMPARs during slow homeostatic forms of synaptic plasticity remain unexplored. Here, we show that, in contrast to LTD, constitutive AMPAR internalization and homeostatic AMPAR downscaling in rat neurons do not require dynamin or clathrin function. Instead, constitutive AMPAR trafficking is blocked by a Rac1 inhibitor and is regulated by a dynamic nonstructural pool of F-actin. Our findings reveal a novel role for neuronal clathrin-independent endocytosis controlled by actin dynamics and suggest that the interplay between different modes of receptor endocytosis provides for segregation between distinct modes of neuronal plasticity.
- Published
- 2015
11. Subunit Dependencies ofN-Methyl-d-aspartate (NMDA) Receptor-Induced α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Internalization
- Author
-
Georg F. Rast, Ralf Schoepfer, Michael G. Stewart, Christian G. Specht, Yves P. Auberson, Agnes Thalhammer, and Cezar M. Tigaret
- Subjects
media_common.quotation_subject ,Green Fluorescent Proteins ,AMPA receptor ,Endocytosis ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Mice ,mental disorders ,Animals ,Receptors, AMPA ,Receptor ,Internalization ,DNA Primers ,media_common ,Neurons ,Pharmacology ,Base Sequence ,Chemistry ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Depolarization ,Cell biology ,Phenotype ,nervous system ,Biochemistry ,Synaptic plasticity ,Molecular Medicine ,NMDA receptor ,biological phenomena, cell phenomena, and immunity ,psychological phenomena and processes - Abstract
N-Methyl-D-aspartate (NMDA) receptor (NMDAR) activity regulates the net number of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) at the cell surface by modulating the balance between AMPAR membrane insertion and endocytosis. In this study, we addressed the role of NMDAR subtypes and of NMDAR-mediated Ca2+ influx in the NMDAR-induced endocytosis of GluR2-containing AMPARs in primary murine hippocampal neurons. We found that NMDAR activation enhanced the endocytosis of AMPARs containing the GluR2 splice variants with short, but not long, cytoplasmic tails. NMDA-induced GluR2 endocytosis was completely inhibited by pharmacological block of NR2B-containing NMDARs. In turn, preferential block of NR2A-containing NMDARs did not affect NMDA-induced AMPAR endocytosis, indicating that AMPAR internalization is controlled by a restricted set of NMDARs. The NMDA-induced GluR2 internalization was also observed in the absence of extracellular Na+ ions, suggesting that membrane depolarization is not a prerequisite for this effect. Furthermore, the activation of Ca2+-impermeable NMDARs containing the mutant NR1(N598R) subunit failed to enhance AMPAR endocytosis, indicating a requirement of Ca2+ influx directly through the NMDAR channels. In summary, our findings suggest that the NMDAR-induced selective internalization of short C-terminal GluR2-containing AMPARs requires a Ca2+ signal that originates from NMDAR channels and is processed in an NMDAR subtype-restricted manner.
- Published
- 2006
12. Subcellular localisation of recombinant α- and γ-synuclein
- Author
-
Georg F. Rast, Cezar M. Tigaret, Ralf Schoepfer, Agnes Thalhammer, Christian G. Specht, and York Rudhard
- Subjects
Alpha-synuclein ,Sindbis virus ,biology ,animal diseases ,Gamma-synuclein ,Wild type ,Cell Biology ,biology.organism_classification ,Fusion protein ,nervous system diseases ,Cell biology ,Cellular and Molecular Neuroscience ,Cell nucleus ,chemistry.chemical_compound ,medicine.anatomical_structure ,Protein structure ,nervous system ,chemistry ,mental disorders ,medicine ,Nuclear protein ,Molecular Biology ,Neuroscience - Abstract
alpha-Synuclein, a protein implicated in neurodegenerative diseases and of elusive physiological function owes its name to an observed presence in presynaptic and nuclear compartments. However, its nuclear localisation has remained controversial. We expressed synuclein-eGFP fusion proteins in organotypic rat hippocampal slice cultures and murine hippocampal primary neurons using a Sindbis virus expression system. Recombinant full-length alpha-synuclein accumulated in presynaptic locations, mimicking its native distribution. Expression of deletion mutant alpha-synuclein revealed that presynaptic targeting depended on the presence of its N-terminal and core region. This domain also causes nuclear exclusion of the alpha-synuclein fusion protein. In contrast, the C-terminal domain of alpha-synuclein directs fusion proteins into the nuclear compartment. The related protein gamma-synuclein contains a similar N-terminal and core domain as alpha-synuclein. However, gamma-synuclein lacks a C-terminal domain that causes nuclear localisation of the fusion protein, suggesting that the two synucleins might have different roles relating to the cell nucleus. (C) 2004 Elsevier Inc. All rights reserved.
- Published
- 2005
13. Wavelet Transform-Based De-Noising for Two-Photon Imaging of Synaptic Ca 2+ Transients
- Author
-
Graham L. Collingridge, Jack R. Mellor, Krasimira Tsaneva-Atanasova, and Cezar M. Tigaret
- Subjects
Male ,Wavelet Analysis ,Analytical chemistry ,Biophysics ,Signal-To-Noise Ratio ,Neurotransmission ,Biology ,Hippocampus ,Signal ,Signal-to-noise ratio ,Wavelet ,Distortion ,Animals ,Calcium Signaling ,Channels and Transporters ,Rats, Wistar ,Neurons ,Quantitative Biology::Neurons and Cognition ,Noise (signal processing) ,Excitatory Postsynaptic Potentials ,Wavelet transform ,Filter (signal processing) ,Rats ,Microscopy, Fluorescence, Multiphoton ,Synapses ,Calcium ,Biological system ,Algorithms - Abstract
Postsynaptic Ca(2+) transients triggered by neurotransmission at excitatory synapses are a key signaling step for the induction of synaptic plasticity and are typically recorded in tissue slices using two-photon fluorescence imaging with Ca(2+)-sensitive dyes. The signals generated are small with very low peak signal/noise ratios (pSNRs) that make detailed analysis problematic. Here, we implement a wavelet-based de-noising algorithm (PURE-LET) to enhance signal/noise ratio for Ca(2+) fluorescence transients evoked by single synaptic events under physiological conditions. Using simulated Ca(2+) transients with defined noise levels, we analyzed the ability of the PURE-LET algorithm to retrieve the underlying signal. Fitting single Ca(2+) transients with an exponential rise and decay model revealed a distortion of τ(rise) but improved accuracy and reliability of τ(decay) and peak amplitude after PURE-LET de-noising compared to raw signals. The PURE-LET de-noising algorithm also provided a ∼30-dB gain in pSNR compared to ∼16-dB pSNR gain after an optimized binomial filter. The higher pSNR provided by PURE-LET de-noising increased discrimination accuracy between successes and failures of synaptic transmission as measured by the occurrence of synaptic Ca(2+) transients by ∼20% relative to an optimized binomial filter. Furthermore, in comparison to binomial filter, no optimization of PURE-LET de-noising was required for reducing arbitrary bias. In conclusion, the de-noising of fluorescent Ca(2+) transients using PURE-LET enhances detection and characterization of Ca(2+) responses at central excitatory synapses.
- Published
- 2013
14. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin
- Author
-
Cezar M. Tigaret, Paul De Koninck, Patricio Opazo, Daniel Choquet, Paul W. Wiseman, Arnaud Frouin, and Simon Labrecque
- Subjects
Benzylamines ,Action Potentials ,Hippocampus ,Diffusion ,Rats, Sprague-Dawley ,0302 clinical medicine ,Postsynaptic potential ,Phosphorylation ,Cells, Cultured ,Neurons ,0303 health sciences ,Sulfonamides ,Chemistry ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Glutamate receptor ,Intracellular Signaling Peptides and Proteins ,Cell biology ,Protein Transport ,SIGNALING ,Disks Large Homolog 4 Protein ,Binding domain ,Neuroscience(all) ,PDZ domain ,Green Fluorescent Proteins ,AMPA receptor ,Benzothiadiazines ,Transfection ,Models, Biological ,MOLNEURO ,Statistics, Nonparametric ,03 medical and health sciences ,Ca2+/calmodulin-dependent protein kinase ,Animals ,Receptors, AMPA ,Protein Kinase Inhibitors ,030304 developmental biology ,Excitatory Postsynaptic Potentials ,Membrane Proteins ,Embryo, Mammalian ,Electric Stimulation ,Rats ,Enzyme Activation ,nervous system ,Animals, Newborn ,Calcium ,Calcium Channels ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,030217 neurology & neurosurgery - Abstract
SummaryThe Ca2+/calmodulin-dependent protein kinase II (CaMKII) is critically required for the synaptic recruitment of AMPA-type glutamate receptors (AMPARs) during both development and plasticity. However, the underlying mechanism is unknown. Using single-particle tracking of AMPARs, we show that CaMKII activation and postsynaptic translocation induce the synaptic trapping of AMPARs diffusing in the membrane. AMPAR immobilization requires both phosphorylation of the auxiliary subunit Stargazin and its binding to PDZ domain scaffolds. It does not depend on the PDZ binding domain of GluA1 AMPAR subunit nor its phosphorylation at Ser831. Finally, CaMKII-dependent AMPAR immobilization regulates short-term plasticity. Thus, NMDA-dependent Ca2+ influx in the post-synapse triggers a CaMKII- and Stargazin-dependent decrease in AMPAR diffusional exchange at synapses that controls synaptic function.
- Published
- 2010
15. Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus
- Author
-
Alexander J. Annala, Ralf Schoepfer, Christian G. Specht, Richard G. M. Morris, Timothy V. P. Bliss, Philip E. Chen, Cezar M. Tigaret, Guiquan Chen, M.L. Errington, Mohammed A. Nassar, Matthias Kneussel, York Rudhard, and Georg F. Rast
- Subjects
Cognitive Neuroscience ,Population ,Blotting, Western ,Long-Term Potentiation ,Hippocampus ,Hippocampal formation ,Biology ,Receptors, N-Methyl-D-Aspartate ,Cellular and Molecular Neuroscience ,Mice ,Animals ,Learning ,education ,Oligonucleotide Array Sequence Analysis ,education.field_of_study ,Neuronal Plasticity ,Behavior, Animal ,Reverse Transcriptase Polymerase Chain Reaction ,Dentate gyrus ,Gene Expression Profiling ,Research ,musculoskeletal, neural, and ocular physiology ,Long-term potentiation ,Immunohistochemistry ,Mice, Mutant Strains ,Neuropsychology and Physiological Psychology ,nervous system ,Synaptic plasticity ,Mutation ,NMDA receptor ,Synaptic signaling ,Neuroscience - Abstract
The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1N598R allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.
- Published
- 2009
16. The glutamate receptor 2 subunit controls post-synaptic density complexity and spine shape in the dentate gyrus
- Author
-
Nikolay I, Medvedev, José J, Rodríguez-Arellano, Victor I, Popov, Heather A, Davies, Cezar M, Tigaret, Ralf, Schoepfer, and Michael G, Stewart
- Subjects
Male ,Mice, Knockout ,Mice ,Gene Expression Regulation ,Dendritic Spines ,Dentate Gyrus ,Synapses ,Animals ,Receptors, AMPA - Abstract
In adult brain the majority of AMPA glutamate receptor (GluR) subunits contain GluR2. In knock-out (KO) mice the absence of GluR2 results in consequences for synaptic plasticity including cognitive impairments. Here the morphology of dendritic spines and their synaptic contacts was analysed via three-dimensional reconstruction of serial electron micrographs from dentate gyrus (DG) of adult wild type (WT) and GluR2 KO mice. Pre-embedding immunocytochemical staining was used to examine the distribution and subcellular localization of AMPA receptor GluR1 and N-methyl-D-aspartate receptor NR1 subunits. There were no significant changes in synapse density in the DG of GluR2 KO compared with WT mice. However, in GluR2 KO mice there was a significant decrease in the percentage of synapses on mushroom spines but an increase in synapses on thin spines. There was also a large decrease in the proportion of synapses with complex perforated/segmented post-synaptic densities (PSDs) (25 vs. 78% in WT) but an increase in synapses with macular PSDs (75 vs. 22%). These data were coupled in GluR2 KO mice with significant decreases in volume and surface area of mushroom spines and their PSDs. In both GluR2 KO and WT mice, NR1 and GluR1 receptors were present in dendrites and spines but there was a significant reduction in NR1 labelling of spine membranes and cytoplasm in GluR2 KO mice, and a small decrease in GluR1 immunolabelling in membranes and cytoplasm of spines in GluR2 KO compared with WT mice. Our data demonstrate that the absence of GluR2 has a significant effect on both DG synapse and spine cytoarchitecture and the expression of NR1 receptors.
- Published
- 2008
17. CaMKII translocation requires local NMDA receptor-mediated Ca2+ signaling
- Author
-
Cezar M. Tigaret, Dmitri A. Rusakov, Kirill E. Volynski, Ralf Schoepfer, Agnes Thalhammer, and York Rudhard
- Subjects
Dendritic spine ,N-Methylaspartate ,Dendritic Spines ,Models, Neurological ,Biology ,Arginine ,Receptors, N-Methyl-D-Aspartate ,General Biochemistry, Genetics and Molecular Biology ,Article ,Mice ,Ca2+/calmodulin-dependent protein kinase ,Animals ,Calcium Signaling ,Molecular Biology ,Calcium signaling ,General Immunology and Microbiology ,General Neuroscience ,musculoskeletal, neural, and ocular physiology ,Autophosphorylation ,Glutamate receptor ,Long-term potentiation ,Cell biology ,Protein Transport ,nervous system ,Calcium-Calmodulin-Dependent Protein Kinases ,Synapses ,NMDA receptor ,Mutant Proteins ,biological phenomena, cell phenomena, and immunity ,Calcium-Calmodulin-Dependent Protein Kinase Type 2 ,Postsynaptic density - Abstract
Excitatory synaptic transmission and plasticity are critically modulated by N-methyl-D-aspartate receptors (NMDARs). Activation of NMDARs elevates intracellular Ca(2+) affecting several downstream signaling pathways that involve Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Importantly, NMDAR activation triggers CaMKII translocation to synaptic sites. NMDAR activation failed to induce Ca(2+) responses in hippocampal neurons lacking the mandatory NMDAR subunit NR1, and no EGFP-CaMKIIalpha translocation was observed. In cells solely expressing Ca(2+)-impermeable NMDARs containing NR1(N598R)-mutant subunits, prolonged NMDA application elevated internal Ca(2+) to the same degree as in wild-type controls, yet failed to translocate CaMKIIalpha. Brief local NMDA application evoked smaller Ca(2+) transients in dendritic spines of mutant compared to wild-type cells. CaMKIIalpha mutants that increase binding to synaptic sites, namely CaMKII-T286D and CaMKII-TT305/306VA, rescued the translocation in NR1(N598R) cells in a glutamate receptor-subtype-specific manner. We conclude that CaMKII translocation requires Ca(2+) entry directly through NMDARs, rather than other Ca(2+) sources activated by NMDARs. Together with the requirement for activated, possibly ligand-bound, NMDARs as CaMKII binding partners, this suggests that synaptic CaMKII accumulation is an input-specific signaling event.
- Published
- 2006
18. Subcellular localisation of recombinant alpha- and gamma-synuclein
- Author
-
Christian G, Specht, Cezar M, Tigaret, Georg F, Rast, Agnes, Thalhammer, York, Rudhard, and Ralf, Schoepfer
- Subjects
Cell Nucleus ,Male ,Recombinant Fusion Proteins ,Genetic Vectors ,Active Transport, Cell Nucleus ,Presynaptic Terminals ,Synucleins ,Mice, Transgenic ,Nerve Tissue Proteins ,Hippocampus ,Cell Compartmentation ,Protein Structure, Tertiary ,Rats ,Mice, Inbred C57BL ,Rats, Sprague-Dawley ,Mice ,gamma-Synuclein ,Animals, Newborn ,Mutation ,alpha-Synuclein ,Animals ,Cells, Cultured - Abstract
alpha-Synuclein, a protein implicated in neurodegenerative diseases and of elusive physiological function owes its name to an observed presence in presynaptic and nuclear compartments. However, its nuclear localisation has remained controversial. We expressed synuclein-eGFP fusion proteins in organotypic rat hippocampal slice cultures and murine hippocampal primary neurons using a Sindbis virus expression system. Recombinant full-length alpha-synuclein accumulated in presynaptic locations, mimicking its native distribution. Expression of deletion mutant alpha-synuclein revealed that presynaptic targeting depended on the presence of its N-terminal and core region. This domain also causes nuclear exclusion of the alpha-synuclein fusion protein. In contrast, the C-terminal domain of alpha-synuclein directs fusion proteins into the nuclear compartment. The related protein gamma-synuclein contains a similar N-terminal and core domain as alpha-synuclein. However, gamma-synuclein lacks a C-terminal domain that causes nuclear localisation of the fusion protein, suggesting that the two synucleins might have different roles relating to the cell nucleus.
- Published
- 2004
19. K+- Channel Openers Protect the Myocardium against Ischemia-Reperfusion Injury
- Author
-
M. Popescu, Ion I. Moraru, S. Musat, Mircea Leabu, Mihail Eugen Hinescu, O. C. Trifan, Cezar M. Tigaret, Laurenţiu M. Popescu, Dipak K. Das, and Alexandru Cristian Popescu
- Subjects
medicine.medical_specialty ,Chemistry ,business.industry ,General Neuroscience ,Ischemia ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Text mining ,History and Philosophy of Science ,Internal medicine ,medicine ,Cardiology ,business ,Reperfusion injury ,K channels - Published
- 1994
20. More AMPAR Garnish
- Author
-
Cezar M. Tigaret and Daniel Choquet
- Subjects
chemistry.chemical_compound ,Multidisciplinary ,Amino Acid Motifs ,Protein family ,chemistry ,Excitatory synaptic transmission ,Glutamate receptor ,AMPA receptor ,Neurotransmission ,Neurotransmitter ,Receptor ,Cell biology - Abstract
Two protein families control excitatory synaptic transmission by receptors for the neurotransmitter glutamate.
- Published
- 2009
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.