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https://www.readbyqxmd.com/read/28543279/role-of-ampa-receptors-in-homocysteine-nmdar-induced-crosstalk-between-erk-and-p38-map-kinase
#1
Ranjana Poddar, Alexandria Chen, Lucas Winter, Sathyanarayanan Rajagopal, Surojit Paul
Homocysteine, a metabolite of the methionine cycle has been reported to play a role in neurotoxicity through activation of NMDAR-mediated signaling pathway. The proposed mechanisms associated with homocysteine-NMDAR induced neurotoxicity involve a unique signaling pathway that triggers a crosstalk between ERK and p38 MAPKs, where activation of p38 MAPK is downstream of and dependent on ERK MAPK. However, the molecular basis of the ERK MAPK mediated p38 MAPK activation is not understood. The current study investigates whether AMPARs play a role in facilitating the ERK MAPK mediated p38 MAPK activation...
May 24, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28541473/relationship-between-synaptic-ampar-and-spine-dynamics-impairments-in-the-fxs-mouse
#2
Anand Suresh, Anna Dunaevsky
Structural dynamics of dendritic spines are important for memory and learning and are impaired in neurodevelopmental disorders such as fragile X syndrome. Spine dynamics are regulated by activity-dependent mechanisms that involve modulation of AMPA receptors (AMPAR); however, the relationship between AMPAR and spine dynamics in vivo and how these are altered in FXS mouse model is not known. Here, we tracked AMPAR and spines over multiple days in vivo in the cortex and found that dendritic spines in the fmr1 KO mouse were denser, smaller, had higher turnover rates and contained less sGluA2 compared to littermate controls...
May 24, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28539424/ca-2-permeable-ampars-mediate-glutamatergic-transmission-and-excitotoxic-damage-at-the-hair-cell-ribbon-synapse
#3
Joy Y Sebe, Soyoun Cho, Lavinia Sheets, Mark A Rutherford, Henrique von Gersdorff, David W Raible
We report functional and structural evidence for GluA2-lacking Ca(2+)-permeable AMPARs (CP-AMPARs) at the mature hair cell ribbon synapse. By utilizing the methodological advantages of three species (of either sex), we demonstrate that CP-AMPARs are present at the hair cell synapse in an evolutionarily conserved manner. Via a combination of in vivo electrophysiological and Ca(2+) imaging approaches in the larval zebrafish, we show that hair cell stimulation leads to robust Ca(2+) influx into afferent terminals...
May 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28521126/structural-and-functional-architecture-of-ampa-type-glutamate-receptors-and-their-auxiliary-proteins
#4
REVIEW
Ingo H Greger, Jake F Watson, Stuart G Cull-Candy
AMPA receptors (AMPARs) are tetrameric ion channels that together with other ionotropic glutamate receptors (iGluRs), the NMDA and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. Whereas NMDA receptors gate channels with slow kinetics, responsible primarily for generating long-term synaptic potentiation and depression, AMPARs are the main fast transduction elements at synapses and are critical for the expression of plasticity. The kinetic and conductance properties of AMPARs are laid down during their biogenesis and are regulated by post-transcriptional RNA editing, splice variation, post-translational modification, and subunit composition...
May 17, 2017: Neuron
https://www.readbyqxmd.com/read/28513836/facilitation-of-mossy-fibre-driven-spiking-in-the-cerebellar-nuclei-by-the-synchrony-of-inhibition
#5
Yeechan Wu, Indira M Raman
Large projection neurons of the cerebellar nuclei (CbN cells), whose activity generates movement, are inhibited by Purkinje cells and excited by mossy fibres. The high convergence, firing rates, and strength of Purkinje inputs predict powerful suppression of CbN cell spiking, raising the question of what activity patterns favor excitation over inhibition. Recording from CbN cells at near-physiological temperatures in cerebellar slices from weanling mice, we measured the amplitude, kinetics, voltage-dependence, and short-term plasticity of mossy fibre-mediated EPSCs...
May 17, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28507080/divergent-roles-of-a-peripheral-transmembrane-segment-in-ampa-and-nmda-receptors
#6
Johansen B Amin, Catherine L Salussolia, Kelvin Chan, Michael C Regan, Jian Dai, Huan-Xiang Zhou, Hiro Furukawa, Mark E Bowen, Lonnie P Wollmuth
Ionotropic glutamate receptors (iGluRs), including AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subtypes, are ligand-gated ion channels that mediate signaling at the majority of excitatory synapses in the nervous system. The iGluR pore domain is structurally and evolutionarily related to an inverted two-transmembrane K(+) channel. Peripheral to the pore domain in eukaryotic iGluRs is an additional transmembrane helix, the M4 segment, which interacts with the pore domain of a neighboring subunit. In AMPARs, the integrity of the alignment of a specific face of M4 with the adjacent pore domain is essential for receptor oligomerization...
May 15, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28497801/pde4-inhibition-restores-the-balance-between-excitation-and-inhibition-in-vta-dopamine-neurons-disrupted-by-repeated-in-vivo-cocaine-exposure
#7
Xiaojie Liu, Peng Zhong, Casey Vickstrom, Yan Li, Qing-Song Liu
Phosphodiesterase type 4 (PDE4) is a family of enzymes that selectively degrade intracellular cAMP. PDE4 inhibitors have been shown to regulate the rewarding and reinforcing effects of cocaine, but the underlying mechanisms remain poorly understood. Here we show that pretreatments with the PDE4 inhibitor rolipram attenuated cocaine-induced locomotor sensitization in mice. Repeated cocaine exposure in vivo caused a decrease in inhibitory postsynaptic currents (IPSCs) and an increase in the AMPAR/NMDAR ratio in ventral tegmental area (VTA) dopamine neurons in midbrain slices ex vivo...
May 12, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28496171/altered-balance-of-excitatory-and-inhibitory-learning-in-a-genetically-modified-mouse-model-of-glutamatergic-dysfunction-relevant-to-schizophrenia
#8
David J Sanderson, Aletheia Lee, Rolf Sprengel, Peter H Seeburg, Paul J Harrison, David M Bannerman
The GluA1 AMPAR subunit (encoded by the Gria1 gene) has been implicated in schizophrenia. Gria1 knockout in mice results in recently experienced stimuli acquiring aberrantly high salience. This suggests that GluA1 may be important for learning that is sensitive to the temporal contiguity between events. To test this, mice were trained on a Pavlovian trace conditioning procedure in which the presentation of an auditory cue and food were separated by a temporal interval. Wild-type mice initially learnt, but with prolonged training came to withhold responding during the trace-conditioned cue, responding less than for another cue that was nonreinforced...
May 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28494864/distinct-translaminar-glutamatergic-circuits-to-gabaergic-interneurons-in-the-neonatal-auditory-cortex
#9
Rongkang Deng, Joseph P Y Kao, Patrick O Kanold
GABAergic activity is important in neocortical development and plasticity. Because the maturation of GABAergic interneurons is regulated by neural activity, the source of excitatory inputs to GABAergic interneurons plays a key role in development. We show, by laser-scanning photostimulation, that layer 4 and layer 5 GABAergic interneurons in the auditory cortex in neonatal mice (<P7) receive extensive translaminar glutamatergic input via NMDAR-only synapses. Extensive translaminar AMPAR-mediated input developed during the second postnatal week, whereas NMDAR-only presynaptic connections decreased...
May 9, 2017: Cell Reports
https://www.readbyqxmd.com/read/28481031/interleukin-6-trans-signaling-regulates-basal-synaptic-transmission-and-sensitivity-to-pentylenetetrazole-induced-seizures-in-mice
#10
Roberto Cuevas-Olguin, Eric Esquivel-Rendon, Jorge Vargas-Mireles, Francisco Garcias-Oscos, Marcela Miranda-Morales, Humberto Salgado, Stefan Rose-John, Marco Atzori
The pro-inflammatory cytokine interleukin 6 (IL-6) interacts with the central nervous system in a largely unknown manner. We used a genetically modified mouse strain (GFAP-sgp130Fc, TG) and wild type (WT) mice to determine whether IL-6 trans-signaling contributes to basal properties of synaptic transmission. Postsynaptic currents (PSCs) were studied by patch-clamp recording in cortical layer 5 of a mouse prefrontal cortex brain slice preparation. TG and WT animals displayed differences mainly (but not exclusively) in excitatory synaptic responses...
May 8, 2017: Synapse
https://www.readbyqxmd.com/read/28474392/detection-and-characterization-of-individual-endocytosis-of-ampa-type-glutamate-receptor-around-postsynaptic-membrane
#11
Shumpei Fujii, Hiromitsu Tanaka, Tomoo Hirano
Synaptic plasticity such as long-term depression (LTD) has been regarded as a cellular mechanism of learning and memory. LTD is expressed by the decrease in number of postsynaptic AMPA-type receptor (AMPAR) at glutamatergic synapses. Although endocytosis is known to play an essential role in the decrease in AMPAR on postsynaptic membrane, the difficulty to detect individual endocytic events hampered clarification of AMPAR dynamics around synapses. Previously, we developed a method to induce formation of postsynaptic-like membrane (PSLM) on the glass surface and observed pHluorin-tagged AMPAR around PSLM with total internal reflection fluorescence microscopy...
May 5, 2017: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/28472657/structural-bases-of-desensitization-in-ampa-receptor-auxiliary-subunit-complexes
#12
Edward C Twomey, Maria V Yelshanskaya, Robert A Grassucci, Joachim Frank, Alexander I Sobolevsky
Fast excitatory neurotransmission is mediated by AMPA-subtype ionotropic glutamate receptors (AMPARs). AMPARs, localized at post-synaptic densities, are regulated by transmembrane auxiliary subunits that modulate AMPAR assembly, trafficking, gating, and pharmacology. Aberrancies in AMPAR-mediated signaling are associated with numerous neurological disorders. Here, we report cryo-EM structures of an AMPAR in complex with the auxiliary subunit GSG1L in the closed and desensitized states. GSG1L favors the AMPAR desensitized state, where channel closure is facilitated by profound structural rearrangements in the AMPAR extracellular domain, with ligand-binding domain dimers losing their local 2-fold rotational symmetry...
May 3, 2017: Neuron
https://www.readbyqxmd.com/read/28457974/a-novel-nmda-receptor-positive-allosteric-modulator-that-acts-via-the-transmembrane-domain
#13
Tzu-Ming Wang, Brandon M Brown, Lunbin Deng, Benjamin D Sellers, Patrick J Lupardus, Heidi J A Wallweber, Amy Gustafson, Evera Wong, Matthew Volgraf, Jacob B Schwarz, David H Hackos, Jesse E Hanson
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory neurotransmission and are key nervous system drug targets. While diverse pharmacological tools have yielded insight into iGluR extracellular domain function, less is known about molecular mechanisms underlying the ion conduction gating process within the transmembrane domain (TMD). We have discovered a novel NMDAR positive allosteric modulator (PAM), GNE-9278, with a unique binding site on the extracellular surface of the TMD. Mutation of a single residue near the Lurcher motif on GluN1 M3 can convert GNE-9278 modulation from positive to negative, and replacing three AMPAR pre-M1 residues with corresponding NMDAR residues can confer GNE-9278 sensitivity to AMPARs...
April 27, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28453662/mglur5-tunes-ngf-trka-signaling-to-orient-spiny-stellate-neuron-dendrites-toward-thalamocortical-axons-during-whisker-barrel-map-formation
#14
Jui-Yen Huang, Hui-Chen Lu
Neurons receive and integrate synaptic inputs at their dendrites, thus dendritic patterning shapes neural connectivity and behavior. Aberrant dendritogenesis is present in neurodevelopmental disorders such as Down's syndrome and autism. Abnormal glutamatergic signaling has been observed in these diseases, as has dysfunction of the metabotropic glutamate receptor 5 (mGluR5). Deleting mGluR5 in cortical glutamatergic neurons disrupted their coordinated dendritic outgrowth toward thalamocortical axons and perturbed somatosensory circuits...
April 27, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28416811/gene-deficiency-and-pharmacological-inhibition-of-caspase-1-confers-resilience-to-chronic-social-defeat-stress-via-regulating-the-stability-of-surface-ampars
#15
M-X Li, H-L Zheng, Y Luo, J-G He, W Wang, J Han, L Zhang, X Wang, L Ni, H-Y Zhou, Z-L Hu, P-F Wu, Y Jin, L-H Long, H Zhang, G Hu, J-G Chen, F Wang
Both inflammatory processes and glutamatergic systems have been implicated in the pathophysiology of mood-related disorders. However, the role of caspase-1, a classic inflammatory caspase, in behavioral responses to chronic stress remains largely unknown. To address this issue, we examined the effects and underlying mechanisms of caspase-1 on preclinical murine models of depression. We found that loss of caspase-1 expression in Caspase-1(-/-) knockout mice alleviated chronic stress-induced depression-like behaviors, whereas overexpression of caspase-1 in the hippocampus of wild-type (WT) mice was sufficient to induce depression- and anxiety-like behaviors...
April 18, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28412220/inflammation-induced-glua1-trafficking-and-membrane-insertion-of-ca-2-permeable-ampa-receptors-in-dorsal-horn-neurons-is-dependent-on-spinal-tumor-necrosis-factor-pi3-kinase-and-protein-kinase-a
#16
G Wigerblad, J R Huie, H Z Yin, M Leinders, R A Pritchard, F J Koehrn, W-H Xiao, G J Bennett, R L Huganir, A R Ferguson, J H Weiss, C I Svensson, L S Sorkin
Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca(2+) permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. Levels of GluA1 and GluA4 from dorsal spinal membrane fractions increased in carrageenan-injected rats compared to controls...
April 12, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28401316/the-orally-active-noncompetitive-ampar-antagonist-perampanel-attenuates-focal-cerebral-ischemia-injury-in-rats
#17
Hong-Xia Niu, Jun-Zhe Wang, Dong-Liang Wang, Jun-Jie Miao, Hua Li, Zhi-Gang Liu, Xing Yuan, Wei Liu, Jing-Ru Zhou
Inhibition of ionotropic glutamate receptors (iGluRs) is a potential target of therapy for ischemic stroke. Perampanel is a potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist with good oral bioavailability and favorable pharmacokinetic properties. Here, we investigated the potential protective effects of perampanel against focal cerebral ischemia in a middle cerebral artery occlusion (MCAO) model in rats. Oral administration with perampanel significantly reduced MCAO-induced brain edema, brain infarct volume, and neuronal apoptosis...
April 11, 2017: Cellular and Molecular Neurobiology
https://www.readbyqxmd.com/read/28397107/the-number-and-distribution-of-ampa-receptor-channels-containing-fast-kinetic-glua3-and-glua4-subunits-at-auditory-nerve-synapses-depend-on-the-target-cells
#18
María E Rubio, Ko Matsui, Yugo Fukazawa, Naomi Kamasawa, Harumi Harada, Makoto Itakura, Elek Molnár, Manabu Abe, Kenji Sakimura, Ryuichi Shigemoto
The neurotransmitter receptor subtype, number, density, and distribution relative to the location of transmitter release sites are key determinants of signal transmission. AMPA-type ionotropic glutamate receptors (AMPARs) containing GluA3 and GluA4 subunits are prominently expressed in subsets of neurons capable of firing action potentials at high frequencies, such as auditory relay neurons. The auditory nerve (AN) forms glutamatergic synapses on two types of relay neurons, bushy cells (BCs) and fusiform cells (FCs) of the cochlear nucleus...
April 10, 2017: Brain Structure & Function
https://www.readbyqxmd.com/read/28387242/chemical-labelling-for-visualizing-native-ampa-receptors-in-live-neurons
#19
Sho Wakayama, Shigeki Kiyonaka, Itaru Arai, Wataru Kakegawa, Shinji Matsuda, Keiji Ibata, Yuri L Nemoto, Akihiro Kusumi, Michisuke Yuzaki, Itaru Hamachi
The location and number of neurotransmitter receptors are dynamically regulated at postsynaptic sites. However, currently available methods for visualizing receptor trafficking require the introduction of genetically engineered receptors into neurons, which can disrupt the normal functioning and processing of the original receptor. Here we report a powerful method for visualizing native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) which are essential for cognitive functions without any genetic manipulation...
April 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28385956/deconstructing-behavioral-neuropharmacology-with-cellular-specificity
#20
Brenda C Shields, Elizabeth Kahuno, Charles Kim, Pierre F Apostolides, Jennifer Brown, Sarah Lindo, Brett D Mensh, Joshua T Dudman, Luke D Lavis, Michael R Tadross
Behavior has molecular, cellular, and circuit determinants. However, because many proteins are broadly expressed, their acute manipulation within defined cells has been difficult. Here, we combined the speed and molecular specificity of pharmacology with the cell type specificity of genetic tools. DART (drugs acutely restricted by tethering) is a technique that rapidly localizes drugs to the surface of defined cells, without prior modification of the native target. We first developed an AMPAR antagonist DART, with validation in cultured neuronal assays, in slices of mouse dorsal striatum, and in behaving mice...
April 7, 2017: Science
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