2007;30:407C416. 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 interpersonal and economic burden. The purpose Arteether of this article is to provide an overview of the molecular and cellular AMPA receptor trafficking events that control synaptic responsiveness and plasticity, and spotlight what is known currently known about how these processes change with age and Arteether disease. Applied to multiple synapses across a group of neurons, it gave rise to the concept that memories are encoded as engrams, which are biophysical changes to a neuronal network.5 Experimental proof of experience-dependent Hebbian plasticity was first obtained in 1973 when it was shown that repeated stimulation of presynaptic perforant path cells in the hippocampus caused lasting increases in postsynaptic responses in dentate gyrus neurons in anesthetized rabbits.6 A diverse range of Hebbian and non-Hebbian types of plasticity have since been discovered, but can generally be divided into four main classes: Short-term synaptic plasticity, where activation of a synapse increases or decreases the efficacy of synaptic transmission at that particular synapse for seconds or minutes. Long-term synaptic plasticity, which is like short-term plasticity but where the synapse-specific changes last from minutes to a lifetime.7 Metaplasticity, where synaptic or cellular activity regulates the capacity of individual synapses to undergo subsequent synaptic plasticity. This is sometimes termed the Complex combinations of signaling pathways regulated by global network activity and by the history of activity at the synapse control the number, synaptic localization, and subunit composition of synaptic Rabbit Polyclonal to Cytochrome P450 26C1 AMPARs. Increases in the number as well as changes in the composition and/or properties of synaptic AMPARs mediate LTP and LTD, which occur at synapses throughout the CNS26 Furthermore, as discussed below, aberrant AMPAR trafficking is usually implicated in neurodegenerative diseases. Open in a separate window Physique 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 usually 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. Open in a separate window Physique 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 depressive disorder (LTD). Increased synaptic strength during LTP occurs through an increase in the number of postsynaptic AMPARs, while LTD is usually 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. AMPAR subunit composition, assembly, and ER exit AMPARs assemble in the endoplasmic reticulum (ER) first as dimers, which then come together to form dimers of dimers to make a tetramer.27,28 In Arteether adult rat hippocampal neurons AMPARs mainly comprise combinations of GluA1/2 or GluA2/3 subunits,29 and synaptic AMPARs.