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Joongkyu Park
Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity...
October 8, 2018: Proteomes
Stephen D Glasgow, Simon Labrecque, Ian V Beamish, Sarah Aufmkolk, Julien Gibon, Dong Han, Stephanie N Harris, Paul Dufresne, Paul W Wiseman, R Anne McKinney, Philippe Séguéla, Paul De Koninck, Edward S Ruthazer, Timothy E Kennedy
Dynamic trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) to synapses is critical for activity-dependent synaptic plasticity underlying learning and memory, but the identity of key molecular effectors remains elusive. Here, we demonstrate that membrane depolarization and N-methyl-D-aspartate receptor (NMDAR) activation triggers secretion of the chemotropic guidance cue netrin-1 from dendrites. Using selective genetic deletion, we show that netrin-1 expression by excitatory neurons is required for NMDAR-dependent long-term potentiation (LTP) in the adult hippocampus...
October 2, 2018: Cell Reports
Li Yang, Peiyu Jin, Xiaoyan Wang, Qing Zhou, Xiaoli Lin, Shuhua Xi
Epidemiological studies have reported that highly fluoridated drinking water may significantly decrease the Intelligence Quotient (IQ) of exposed children. It is thought that synaptic plasticity is the basis of learning and memory skills in developing children. However, the effect on synaptic plasticity by activated microglia induced via fluoride treatment is less clear. Our previous research showed that fluoride ions activated microglia which then released pro-inflammatory cytokines. In this study, hippocampal-dependent memory status was evaluated in rat models sub-chronically exposed to fluoride in their drinking water...
September 28, 2018: Neurotoxicology
Mathieu Letellier, Zsófia Szíber, Ingrid Chamma, Camille Saphy, Ioanna Papasideri, Béatrice Tessier, Matthieu Sainlos, Katalin Czöndör, Olivier Thoumine
To better understand the molecular mechanisms by which early neuronal connections mature into synapses, we examined the impact of neuroligin-1 (Nlg1) phosphorylation on synapse differentiation, focusing on a unique intracellular tyrosine (Y782), which differentially regulates Nlg1 binding to PSD-95 and gephyrin. By expressing Nlg1 point mutants (Y782A/F) in hippocampal neurons, we show using imaging and electrophysiology that Y782 modulates the recruitment of functional AMPA receptors (AMPARs). Nlg1-Y782F impaired both dendritic spine formation and AMPAR diffusional trapping, but not NMDA receptor recruitment, revealing the assembly of silent synapses...
September 28, 2018: Nature Communications
Serena Boccella, Claudia Cristiano, Rosaria Romano, Monica Iannotta, Carmela Belardo, Antonio Farina, Francesca Guida, Fabiana Piscitelli, Enza Palazzo, Mariacristina Mazzitelli, Roberta Imperatore, Lea Tunisi, Vito de Novellis, Luigia Cristino, Vincenzo Di Marzo, Antonio Calignano, Sabatino Maione, Livio Luongo
Chronic pain is associated with cognitive deficits. Palmitoylethanolamide (PEA) has been shown to ameliorate pain and pain-related cognitive impairments by restoring glutamatergic synapses functioning in the spared nerve injury (SNI) of the sciatic nerve in mice. SNI reduced mechanical and thermal threshold, spatial memory and LTP at the lateral entorhinal cortex (LEC)-dentate gyrus (DG) pathway. It decreased also postsynaptic density, volume and dendrite arborization of DG and increased the expression of metabotropic glutamate receptor 1 and 7 (mGluR1 and mGluR7), of the GluR1, GluR1s845 and GluR1s831 subunits of AMPA receptor and the levels of glutamate in the DG...
September 25, 2018: Neurobiology of Disease
Ana Del C Vaquer-Alicea, Rafael Vázquez-Torres, Marcos Devarie-Hornedo, Juan C Vicenty-Padilla, Bermary Santos-Vera, Cristina María-Ríos, Maria E Vélez-Hernández, Todd Sacktor, Carlos A Jiménez-Rivera
Chronic cocaine exposure produces enduring neuroadaptations in the brain's reward system. Persistence of early cocaine-evoked neuroadaptations in the ventral tegmental area (VTA) is necessary for later synaptic alterations in the nucleus accumbens (NAc), suggesting a temporal sequence of neuroplastic changes between these two areas. However, the molecular nature of the signal that mediates this sequential event is unknown. Here we used the behavioral sensitization model and the aPKC inhibitor of late-phase LTP maintenance, ZIP, to investigate if a persistent increase in AMPA/NMDA ratio plays a role in the molecular mechanism that allows VTA neuroadaptations to induce changes in the NAc...
September 21, 2018: Neuroscience
Peter V Nguyen, Jennifer N Gelinas
Altered synaptic strength underlies information storage in neural circuits. Neuromodulatory transmitters such as norepinephrine (NE) facilitate long-lasting synaptic plasticity by recruiting and modifying multiple molecular elements of synaptic signaling, including specific transmitter receptors, intracellular protein kinases, and translation initiation. NE regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express β-adrenergic receptors (β-ARs), which bind NE and are critical for gating the induction of long-lasting forms of synaptic potentiation...
September 3, 2018: Journal of Neurogenetics
Xiangdi Yu, Fangxiang Zhang, Jinshan Shi
Anesthetics exposure to neonates leads to impairment of hippocampal synaptic plasticity and cognitive functions later in life. This phenomenon complies with the concept of metaplasticity: a priming stimulation can affect induction of synaptic plasticity mins or days later. We aimed to understand whether small conductance Ca2+ -activated potassium channel type2 (SK2) and subunit composition of AMPA receptors are altered and contribute to sevoflurane-induced metaplasticity. To fulfill this goal, we exposed neonatal rats (postnatal day 7) to 2% sevoflurane for 2 h (sevoflurane rats) and examined synaptic plasticity in the hippocampus and cognitive function in juvenile rats (postnatal day 30-35)...
October 2018: Neuropharmacology
Ibrahim Al-Osta, Mariusz Mucha, Daniel Pereda, Marta Piqué-Gili, Albert E Okorocha, Roisin Thomas, Nicholas A Hartell
Genetically encoded calcium indicators (GECIs) have gained widespread use for measurement of neuronal activity but their low expression levels in transgenic mice tend to limit sensitivity. We have developed a transgenic mouse line (SyG37) that expresses a ratiometric calcium sensor, SyGCaMP2-mCherry, that is expressed throughout the brain but targeted to presynaptic terminals. Within the CA1 and CA3 regions of hippocampus of male and female mice, SyGaMP2 fluorescence responds linearly up to 10 electrical stimuli at frequencies up to 100 Hz and it can detect responses to a single stimulus...
2018: Frontiers in Cellular Neuroscience
Tingting Zhang, Zhaochun Shi, Ya Wang, Ling Wang, Baofeng Zhang, Guiquan Chen, Qi Wan, Ling Chen
AIM: Loss-of-function mutation of Akt3 in humans has been associated with microcephaly and cognitive defects. Two Akt isoforms, Akt1 and Akt3, are highly expressed in hippocampal pyramidal cells. We explored the roles of Akt1 and Akt3, respectively, in spatial cognition and underlying mechanisms. METHODS: We used Akt1 knockout (Akt1-KO) and Akt3 knockout (Akt3-KO) mice to examine the influence of Akt1 and Akt3 deficiency on spatial memory, as well as induction and maintenance of hippocampal CA1 NMDA receptor-dependent and protein synthesis-dependent long-term potentiation (LTP)...
July 27, 2018: Acta Physiologica
Blanka R Szulc, Stephen T Hilton, Arnaud J Ruiz
We have synthesized a novel small molecule based on the pyrrolidinone-containing core structure of clausenamide, which is a candidate anti-dementia drug. The synthetic route yielded multi-gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor-mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l-glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices...
October 2018: Molecular and Cellular Neurosciences
Chen Tian, Yuni Kay, Anastasiia Sadybekov, Sadhna Rao, Vsevolod Katritch, Bruce E Herring
The small GTPase Rac1 promotes actin polymerization and plays a critical and increasingly appreciated role in the development and plasticity of glutamatergic synapses. Growing evidence suggests that disruption of the Rac1 signaling pathway at glutamatergic synapses contributes to Autism Spectrum Disorder/intellectual disability (ASD/ID)-related behaviors seen in animal models of ASD/ID. Rac1 has also been proposed as a strong candidate of convergence for many factors implicated in the development of ASD/ID...
2018: Frontiers in Molecular Neuroscience
Gerhard Rammes, Franziska Seeser, Korinna Mattusch, Kaichuan Zhu, Laura Haas, Markus Kummer, Michael Heneka, Jochen Herms, Chris G Parsons
Aβ1-42 is well accepted to be a primary early pathogenic agent in Alzheimer's disease (AD). However, other amyloid peptides are now gaining considerable attention as potential key participants in AD due to their proposed higher neuronal toxicity. Impairment of the glutamatergic system is also widely accepted to be associated with pathomechanisms underlying AD. There is ample evidence that Aβ1-42 affects GLUN2B subunit containing N-methyl-D-aspartate receptor function and abolishes the induction of long term potentiation (LTP)...
September 15, 2018: Neuropharmacology
David M Bannerman, Thilo Borchardt, Vidar Jensen, Andrey Rozov, Nadia N Haj-Yasein, Nail Burnashev, Daniel Zamanillo, Thorsten Bus, Isabel Grube, Giselind Adelmann, J Nicholas P Rawlins, Rolf Sprengel
The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice ( Gria1R/R ), expressing the "trafficking compromised" GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice...
2018: Frontiers in Molecular Neuroscience
Samantha Baron, Roberto A Barrero, Michael Black, Matthew I Bellgard, Elsie M S van Dalen, Josephus Fourie, Christine Maritz-Olivier
The widespread geographical distribution of Rhipicephalus decoloratus in southern Africa and its ability to transmit the pathogens causing redwater, gallsickness and spirochaetosis in cattle makes this hematophagous ectoparasite of economic importance. In South Africa, the most commonly used chemical acaricides to control tick populations are pyrethroids and amitraz. The current amitraz resistance mechanism described in R. microplus, from South Africa and Australia, involves mutations in the octopamine receptor, but it is unlikely that this will be the only contributing factor to mediate resistance...
June 18, 2018: International Journal for Parasitology, Drugs and Drug Resistance
G Antunes, F M Simoes-de-Souza
Historically, long-term potentiation (LTP) and long-term depression (LTD), the best-characterized forms of long-term synaptic plasticity, are viewed as experience-dependent and input-specific processes. However, cumulative experimental and theoretical data have demonstrated that LTP and LTD can promote compensatory alterations in non-stimulated synapses. In this work, we have developed a computational model of a tridimensional spiny dendritic segment to investigate the role of AMPA receptor (AMPAR) trafficking during synaptic plasticity at specific synapses and its consequences for the populations of AMPAR at nearby synapses...
July 9, 2018: Scientific Reports
Bo Am Seo, Taesup Cho, Daniel Z Lee, Joong-Jae Lee, Boyoung Lee, Seong-Wook Kim, Hee-Sup Shin, Myoung-Goo Kang
Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting...
July 3, 2018: Proceedings of the National Academy of Sciences of the United States of America
Patricio Opazo, Silvia Viana da Silva, Mario Carta, Christelle Breillat, Steven J Coultrap, Dolors Grillo-Bosch, Matthieu Sainlos, Françoise Coussen, K Ulrich Bayer, Christophe Mulle, Daniel Choquet
Alzheimer's disease (AD) is emerging as a synaptopathology driven by metaplasticity. Indeed, reminiscent of metaplasticity, oligomeric forms of the amyloid-β peptide (oAβ) prevent induction of long-term potentiation (LTP) via the prior activation of GluN2B-containing NMDA receptors (NMDARs). However, the downstream Ca2+ -dependent signaling molecules that mediate aberrant metaplasticity are unknown. In this study, we show that oAβ promotes the activation of Ca2+ /calmodulin-dependent kinase II (CaMKII) via GluN2B-containing NMDARs...
June 12, 2018: Cell Reports
Daniel P Radin, Steven Johnson, Richard Purcell, Arnold S Lippa
Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive allosteric modulators of AMPA-type glutamate receptors...
September 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Rodrigo Bainy Leal, Mark William Lopes, Douglas Affonso Formolo, Cristiane Ribeiro de Carvalho, Alexandre Ademar Hoeller, Alexandra Latini, Daniel Santos Sousa, Peter Wolf, Rui Daniel Prediger, Zuner Assis Bortolotto, Marcelo Neves Linhares, Kátia Lin, Roger Walz
Fear is a conscious state caused by exposure to real or imagined threats that trigger stress responses that affect the body and brain, particularly limbic structures. A sub-group of patients with mesial temporal lobe epilepsy related to hippocampus sclerosis (MTLE-HS) have seizures with fear, which is called ictal fear (IF), due to epileptic activity within the brain defensive survival circuit structures. Synaptic transmission efficacy can be bi-directionally modified through potentiation (long-term potentiation (LTP)) or depression (long-term depression (LTD)) as well as the phosphorylation state of Ser831 and Ser845 sites at the GluA1 subunit of the glutamate AMPA receptors, which has been characterized as a critical event for this synaptic plasticity...
June 7, 2018: Molecular Psychiatry
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