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AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging - PubMed

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AMPA receptor trafficking and the mechanisms underlying synaptic plasticity and cognitive aging

Jeremy M Henley et al. Dialogues Clin Neurosci. 2013 Mar.

Abstract

Even in healthy individuals there is an inexorable agerelated decline in cognitive function. This is due, in large part, to reduced synaptic plasticity caused by changes in the molecular composition of the postsynaptic membrane. AMPA receptors (AMPARs) are glutamate-gated cation channels that mediate the overwhelming majority of fast excitatory transmission in the brain. Changes in AMPAR number and/or function are a core feature of synaptic plasticity and age-related cognitive decline, AMPARs are highly dynamic proteins that are subject to highly controlled trafficking, recycling, and/or degradation and replacement. This active regulation of AMPAR synthesis, targeting, synaptic dwell time, and degradation is fundamentally important for memory formation and storage. Further, aberrant AMPAR trafficking and consequent detrimental changes in synapses are strongly implicated in many brain diseases, which represent a vast social and economic burden. The purpose of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and highlight what is known currently known about how these processes change with age and disease.

Incluso en los sujetos sanos existe una inexorable declinación de la función cognitiva relacionada con la edad. Esta es debida, en gran parte, a una reducción de la plasticidad sináptica causada por cambios en la composición molecular de la membrana post-sináptica. Los receptores AMPA (AMPARs) son canales catiónicos dependientes de glutamato que median la mayor parte de la transmisión excitatoria rápida en el cerebro. Los cambios en el número ylo función de los receptores AMPAR constituyen una característica central de la plasticidad sináptica y de la declinación cognitiva relacionada con la edad. Los AMPARs son proteínas altamente dinámicas que están sujetas a un alto control respecto al transporte, reciclado ylo degradación y reemplazo. Esta regulación activa de la síntesis, localización, tiempo de permanencia en la sinapsis y degradación de AMPAR es de fundamental importancia para la formación y almacenamiento de la memoria. Además, el transporte aberrante de AMPAR y los consecuentes cambios dañinos en las sinapsis se asocian fuertemente con muchas enfermedades cerebrales, las que representan un gran costo social y económico. El propósito de este artículo es aportar una perspectiva de los acontecimientos moleculares y celulares del transporte del receptor AMPA que controlan la respuesta sináptica y la plasticidad, y destacar lo que actualmente se sabe acerca de cómo estos procesos cambian con la edad y la enfermedad.

Le déclin cognitif lié a l'âge, inexorable même chez les individus sains, est dû en grande partie à une diminution de la plasticité synaptique causée par des changements de la composition moléculaire de la membrane post-synaptique. Les récepteurs AMPA (AMPAR) sont des canaux de cations contrôlés par le glutamate qui assurent la médiation de la grande majorité de l'excitation rapide du cerveau. Les modifications en nombre et/ou en fonction des AMPAR sont au coeur de la plasticité synaptique et du déclin cognitif lié á l'age. Les AMPAR sont des protéines extrêmement dynamiques sujettes á une circulation, un recyclage et/ou une dégradation et à une substitution très contrôlés. Cette régulation active de la synthèse, du ciblage, du temps de maintien synaptique et de la dégradation des AMPAR est fondamentalement importante pour le stockage et la formation de la mémoire. De plus, une circulation aberrante des AMPAR et les modifications préjudiciables qui s'en suivent dans les synapses sont forte-ment impliquées dans de nombreuses maladies cérébrales, ce qui représente un lourd fardeau économique et social. Cet article a pour but de présenter la circulation du récepteur moléculaire et cellulaire AMPA qui contrôle la plasticité et la réactivité synaptiques et de souligner les connaissances actuelles sur les changements de ces processus avec l'age et la maladie.

Keywords: AMPA receptor; AMPA receptor trafficking; LTD; LTP; glutamate receptor; protein trafficking; synaptic plasticity.

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Figures

Figure 1.
Figure 1.. AMPAR subunit topology, interacting partners and diverse intracellular c-termini. A) The membrane topology of an AMPA receptor subunit (AMPAR). AMPAR subunits have large extracellular N-termini, three full transmembrane domains, and a cytoplasmic re-entrant loop, which forms the lining of the channel pore and, in GluA2, contains the RNA editing site that determines calcium permeability. The glutamate binding site is formed by the extracellular N-terminus and the loop between the second and third full transmembrane domains. The intracellular c-terminus differs between subunits and binds numerous proteins required for the trafficking and synaptic expression of AMPARs. B) Summary of GluA1 and GluA2 interacting proteins discussed in the text. See text for details. C) The intracellular c-termini of the predominant isoforms of human AMPAR subunits. Amino acid numbers represent positions in the mature protein lacking the signal peptide. Highlighted in GluA1 and GluA2 are proposed phosphorylation sites (blue) and ubiquitination sites (orange) discussed in the text. Underlined in GluA1 -3 are the c-terminal PDZ ligands required for binding PDZ domain-containing proteins.
Figure 2.
Figure 2.. Basic principles of AMPAR trafficking and synaptic plasticity. Long-term changes in synaptic function can be induced by activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors, which alter synaptic strength through regulating the number of postsynaptic AMPA receptors (AMPARs). NMDAR activation leads to calcium influx through the receptor, which, depending on the spatiotemporal activation profile, can initiate long-term potentiation (LTP) or long-term depression (LTD). Increased synaptic strength during LTP occurs through an increase in the number of postsynaptic AMPARs, while LTD is characterized by a decrease in postsynaptic AMPAR number. Enhanced AMPAR number during LTP can be mediated through both exocytosis of AMPARs and/or lateral diffusion of AMPARs within the membrane to the synapse. Conversely, LTD leads to AMPAR diffusion away from the synapse and receptor endocytosis.
Figure 3.
Figure 3.. RNA editing of the GluA2 subunit determines calcium permeability of AMPARs. AMPA receptors (AMPARs) lacking the GluA2 subunit, or an unedited GluA2 subunit are calcium-permeable. However, receptors containing an edited GluA2 subunit do not gate calcium. For simplicity, and because their existence in neurons is unclear, GluA3 homomers, which are calcium permeable, and GluA2 homomers, whose calcium permeability depends on the RNA editing state of the GluA2 subunits involved, are not shown. GluA4 (not shown) behaves identically to GluA1.

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