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Nadia Kafui Adotevi, Beulah Leitch
Absence seizures arise from disturbances within the corticothalamocortical network, however the precise cellular and molecular mechanisms underlying seizure generation arising from different genetic backgrounds are not fully understood. While recent experimental evidence suggests that changes in inhibitory microcircuits in the cortex may contribute to generation of the hallmark spike-wave discharges, it is still unclear if altered cortical inhibition is a result of interneuron dysfunction due to compromised glutamatergic excitation and/or changes in cortical interneuron number...
October 4, 2016: Neuroscience
Sana A Shaikh, Drew M Dolino, Garam Lee, Sudeshna Chatterjee, David M MacLean, Charlotte Flatebo, Christy F Landes, Vasanthi Jayaraman
Fast excitatory synaptic signaling in the mammalian brain is mediated by AMPA-type ionotropic glutamate receptors. In neurons, AMPA receptors co-assemble with auxiliary proteins, such as stargazin, which can markedly alter receptor trafficking and gating. Here, we used luminescence resonance energy transfer measurements to map distances between the full-length, functional AMPA receptor and stargazin expressed in HEK293 cells and to determine the ensemble structural changes in the receptor due to stargazin. In addition, we used single-molecule fluorescence resonance energy transfer to study the structural and conformational distribution of the receptor and how this distribution is affected by stargazin...
October 4, 2016: Cell Reports
Edward W Vogel, Steve H Rwema, David F Meaney, Cameron R Dale Bass, Barclay Morrison
Blast-induced traumatic brain injury (bTBI) is a major threat to United States service members in military conflicts worldwide. The effects of primary blast, caused by the supersonic shockwave interacting with the skull and brain, remain unclear. Our group has previously reported that in vitro primary blast exposure can reduce long-term potentiation (LTP), the electrophysiological correlate of learning and memory, in rat organotypic hippocampal slice cultures (OHSCs) without significant changes to cell viability or basal, evoked neuronal function...
October 13, 2016: Journal of Neurotrauma
Edward C Twomey, Maria V Yelshanskaya, Robert A Grassucci, Joachim Frank, Alexander I Sobolevsky
AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo-electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR...
July 1, 2016: Science
Mengping Wei, Jian Zhang, Moye Jia, Chaojuan Yang, Yunlong Pan, Shuaiqi Li, Yiwen Luo, Junyuan Zheng, Jianguo Ji, Jianguo Chen, Xinli Hu, Jingwei Xiong, Yun Shi, Chen Zhang
In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses...
May 10, 2016: Proceedings of the National Academy of Sciences of the United States of America
Alex G Lee, Roxanne Capanzana, Jacqueline Brockhurst, Michelle Y Cheng, Christine L Buckmaster, Devin Absher, Alan F Schatzberg, David M Lyons
Intermittent mildly stressful situations provide opportunities to learn, practice, and improve coping with gains in subsequent emotion regulation. Here we investigate the effects of learning to cope with stress on anterior cingulate cortex gene expression in monkeys and mice. Anterior cingulate cortex is involved in learning, memory, cognitive control, and emotion regulation. Monkeys and mice were randomized to either stress coping or no-stress treatment conditions. Profiles of gene expression were acquired with HumanHT-12v4...
May 2016: Neurobiology of Learning and Memory
Sarah K Coleman, Ying Hou, Marina Willibald, Artur Semenov, Tommi Möykkynen, Kari Keinänen
AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Tyr-454 and Arg-461, in its ligand binding domain (LBD)...
April 15, 2016: Journal of Biological Chemistry
Thomas P McGee, Cécile Bats, Mark Farrant, Stuart G Cull-Candy
UNLABELLED: AMPA-type glutamate receptors are ligand-gated cation channels responsible for a majority of the fast excitatory synaptic transmission in the brain. Their behavior and calcium permeability depends critically on their subunit composition and the identity of associated auxiliary proteins. Calcium-permeable AMPA receptors (CP-AMPARs) contribute to various forms of synaptic plasticity, and their dysfunction underlies a number of serious neurological conditions. For CP-AMPARs, the prototypical transmembrane AMPAR regulatory protein stargazin, which acts as an auxiliary subunit, enhances receptor function by increasing single-channel conductance, slowing channel gating, increasing calcium permeability, and relieving the voltage-dependent block by endogenous intracellular polyamines...
December 9, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Birbickram Roy, Kazi T Ahmed, Marcus E Cunningham, Jannatul Ferdous, Rajarshi Mukherjee, Wang Zheng, Xing-Zhen Chen, Declan W Ali
Fast excitatory synaptic transmission in the CNS is mediated by the neurotransmitter glutamate, binding to and activating AMPA receptors (AMPARs). AMPARs are known to interact with auxiliary proteins that modulate their behavior. One such family of proteins is the transmembrane AMPA receptor-related proteins, known as TARPs. Little is known about the role of TARPs during development, or about their function in non-mammalian organisms. Here we report the presence of TARPs, specifically the prototypical TARP, stargazin, in developing zebrafish...
May 2016: Developmental Neurobiology
Wenchi Zhang, Jing Wu, Matthew D Ward, Sunggu Yang, Yang-An Chuang, Meifang Xiao, Ruojing Li, Daniel J Leahy, Paul F Worley
Arc is a cellular immediate-early gene (IEG) that functions at excitatory synapses and is required for learning and memory. We report crystal structures of Arc subdomains that form a bi-lobar architecture remarkably similar to the capsid domain of human immunodeficiency virus (HIV) gag protein. Analysis indicates Arc originated from the Ty3/Gypsy retrotransposon family and was "domesticated" in higher vertebrates for synaptic functions. The Arc N-terminal lobe evolved a unique hydrophobic pocket that mediates intermolecular binding with synaptic proteins as resolved in complexes with TARPγ2 (Stargazin) and CaMKII peptides and is essential for Arc's synaptic function...
April 22, 2015: Neuron
Anne-Sophie Hafner, Andrew C Penn, Dolors Grillo-Bosch, Natacha Retailleau, Christel Poujol, Amandine Philippat, Françoise Coussen, Matthieu Sainlos, Patricio Opazo, Daniel Choquet
PSD-95 is a prominent organizer of the postsynaptic density (PSD) that can present a filamentous orientation perpendicular to the plasma membrane. Interactions between PSD-95 and transmembrane proteins might be particularly sensitive to this orientation, as "long" cytoplasmic tails might be required to reach deeper PSD-95 domains. Extension/retraction of transmembrane protein C-tails offer a new way of regulating binding to PSD-95. Using stargazin as a model, we found that enhancing the apparent length of stargazin C-tail through phosphorylation or by an artificial linker was sufficient to potentiate binding to PSD-95, AMPAR anchoring, and synaptic transmission...
April 22, 2015: Neuron
Mark Rigby, Stuart G Cull-Candy, Mark Farrant
Presynaptic ionotropic glutamate receptors (iGluRs) play important roles in the control of synaptogenesis and neurotransmitter release, yet their regulation is poorly understood. In particular, the contribution of transmembrane auxiliary proteins, which profoundly shape the trafficking and gating of somatodendritic iGluRs, is unknown. Here we examined the influence of transmembrane AMPAR regulatory proteins (TARPs) on presynaptic AMPARs in cerebellar molecular layer interneurons (MLIs). 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a partial agonist at TARP-associated AMPARs, enhanced spontaneous GABA release in wild-type mice but not in stargazer mice that lack the prototypical TARP stargazin (γ-2)...
March 11, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Audrey Constals, Andrew C Penn, Benjamin Compans, Estelle Toulmé, Amandine Phillipat, Sébastien Marais, Natacha Retailleau, Anne-Sophie Hafner, Françoise Coussen, Eric Hosy, Daniel Choquet
Short-term plasticity of AMPAR currents during high-frequency stimulation depends not only on presynaptic transmitter release and postsynaptic AMPAR recovery from desensitization, but also on fast AMPAR diffusion. How AMPAR diffusion within the synapse regulates synaptic transmission on the millisecond scale remains mysterious. Using single-molecule tracking, we found that, upon glutamate binding, synaptic AMPAR diffuse faster. Using AMPAR stabilized in different conformational states by point mutations and pharmacology, we show that desensitized receptors bind less stargazin and are less stabilized at the synapse than receptors in opened or closed-resting states...
February 18, 2015: Neuron
Maya Yamazaki, Claire E Le Pichon, Alexander C Jackson, Manuel Cerpas, Kenji Sakimura, Kimberly Scearce-Levie, Roger A Nicoll
Transmembrane AMPA receptor regulatory proteins (TARPs) play an essential role in excitatory synaptic transmission throughout the central nervous system (CNS) and exhibit subtype-specific effects on AMPA receptor (AMPAR) trafficking, gating, and pharmacology. The function of TARPs has largely been determined through work on canonical type I TARPs such as stargazin (TARP γ-2), absent in the ataxic stargazer mouse. Little is known about the function of atypical type II TARPs, such as TARP γ-7, which exhibits variable effects on AMPAR function...
January 27, 2015: Proceedings of the National Academy of Sciences of the United States of America
Surya P Pandey, Rakesh Rai, Pankaj Gaur, S Prasad
AMPA type glutamate receptor (AMPAR) on the post synaptic membrane plays important role in the process of synaptic plasticity involving various scaffolding and trafficking proteins. However, their alterations during development- and aging are not well understood. Here, we report that the expression of AMPAR-GluR2 subunit is gradually up regulated in the hippocampus from 0 day to adult (20 week) and down regulated thereafter in 70 week old male mice. This pattern of GluR2 during development (0-, 7- and 15 day), maturation (45 day) and adult age resembles with similar expression pattern of the scaffolding protein PSD95...
June 2015: Biogerontology
David M MacLean, Swarna S Ramaswamy, Mei Du, James R Howe, Vasanthi Jayaraman
Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) markedly enhance AMPAR function, altering ligand efficacy and receptor gating kinetics and thereby shaping the postsynaptic response. The structural mechanism underlying TARP effects on gating, however, is unknown. Here we find that the prototypical member of the TARP family, stargazin or γ-2, rescues gating deficits in AMPARs carrying mutations that destabilize the closed-cleft states of the ligand-binding domain (LBD), suggesting that stargazin reverses the effects of these mutations and likely stabilizes closed LBD states...
December 2014: Journal of General Physiology
Ting Martin Ma, Bindu D Paul, Chenglai Fu, Shaohui Hu, Heng Zhu, Seth Blackshaw, Herman Wolosker, Solomon H Snyder
D-Serine, an endogenous co-agonist for the glycine site of the synaptic NMDA glutamate receptor, regulates synaptic plasticity and is implicated in schizophrenia. Serine racemase (SR) is the enzyme that converts L-serine to D-serine. In this study, we demonstrate that SR interacts with the synaptic proteins, postsynaptic density protein 95 (PSD-95) and stargazin, forming a ternary complex. SR binds to the PDZ3 domain of PSD-95 through the PDZ domain ligand at its C terminus. SR also binds to the C terminus of stargazin, which facilitates the cell membrane localization of SR and inhibits its activity...
October 24, 2014: Journal of Biological Chemistry
David Soto, Ian D Coombs, Esther Gratacòs-Batlle, Mark Farrant, Stuart G Cull-Candy
Many properties of fast synaptic transmission in the brain are influenced by transmembrane AMPAR regulatory proteins (TARPs) that modulate the pharmacology and gating of AMPA-type glutamate receptors (AMPARs). Although much is known about TARP influence on AMPAR pharmacology and kinetics through their modulation of the extracellular ligand-binding domain (LBD), less is known about their regulation of the ion channel region. TARP-induced modifications in AMPAR channel behavior include increased single-channel conductance and weakened block of calcium-permeable AMPARs (CP-AMPARs) by endogenous intracellular polyamines...
August 27, 2014: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Shinya Kawata, Taisuke Miyazaki, Maya Yamazaki, Takayasu Mikuni, Miwako Yamasaki, Kouichi Hashimoto, Masahiko Watanabe, Kenji Sakimura, Masanobu Kano
Synapse elimination is crucial for precise neural circuit formation during postnatal development. We examined how relative differences in synaptic strengths among competing inputs and/or absolute synaptic strengths contribute to climbing fiber (CF) to Purkinje cell (PC) synapse elimination in the cerebellum. We generated mice with PC-selective deletion of stargazin (TARP γ-2), the major AMPA receptor auxiliary subunit in PCs (γ-2 PC-KO mice). Whereas relative differences between "strong" and "weak" CF-mediated postsynaptic response are preserved, absolute strengths of CF inputs are scaled down globally in PCs of γ-2 PC-KO mice...
August 21, 2014: Cell Reports
Ruijuan Guo, Yujie Zhao, Meijuan Zhang, Yue Wang, Rong Shi, Yang Liu, Jie Xu, Anshi Wu, Yun Yue, Jing Wu, Yun Guan, Yun Wang
BACKGROUND: Stargazin is the first transmembrane protein known to regulate synaptic targeting of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors. However, it is unclear whether regulation of the surface delivery of spinal AMPA receptor subunits by stargazin contributes to postoperative pain development. METHODS: Western blot analysis was used to examine changes in the surface delivery of AMPA receptor subunits, GluR1 and GluR2, in rat dorsal horn...
September 2014: Anesthesiology
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