Developmental and Activity Dependent Regulation of Ionotropic Glutamate Receptors at Synapses

Abstract

Glutamate receptors mediate the majority of excitatory responses in the central nervous system. The establishment and refinement of glutamatergic synaptic connections depend on the concerted actions of α α α α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), N-methyl-D-aspartate (NMDA), and kainate (KA) type ionotropic glutamate receptors (iGluRs) and G-protein coupled metabotropic receptors. While a lot remains to be clarified, the most is known about the mechanisms by which the iGluR subtypes are targeted and how this is influenced by synaptic activity on both short and long time scales. Changes in their subunit compositions are also input specific and developmentally regulated. The identification of key molecular components of the postsynaptic density (PSD) and novel proteins that influence receptor targeting and clustering have started to reveal the underlying molecular mechanisms of the trafficking and targeting of iGluRs. Here we discuss the evidence that these basic mechanisms are used during developmental synaptic plasticity. KEY WORDS: AMPA receptors, glutamate, hippocampal neuron, kainate receptor, LTP, LTD, NMDA receptors, postsynaptic density, receptor targeting, silent synapses, synaptic development DOMAINS: enzymology and protein-protein interaction, molecular biology, protein trafficking, protein transcription, protein transport, transcription and gene regulation signaling, drug receptor, psychopharmacology, cell and tissue culture, cell biology, differentiation and determination, intercellular communication, ion channel function, signaling, cognition, development, intracellular communication, learning and memory, neural networks, synapse formation, trans membrane signaling, embryology, neurology, neuroscience, psychiatry, biochemistry, imaging, microscopy INTRODUCTIONSynapses are modifiable sites of information transfer between neurons. This information transfer is mainly mediated by two neurotransmitters: glutamate and γ-amino-butyric acid (GABA). Glutamate, the major excitatory neurotransmitter, can activate several types of iGluRs, which are named for the agonists that selectively stimulate them: AMPA, NMDA, and KA [1,2,3]. iGluRs Molnar and Isaac: Development of Glutamatergic Synapses TheScientificWorldJOURNAL (2002) 2, 27-47 28 are formed from the presumed tetrameric or pentameric assembly of homologous subunits around a central ion pore [2,3]. The membrane topology of the iGluR subunits consists of a large extracellular amino-terminus, four membrane-associated domains with the second transmembrane domain (TM2) forming a re-entrant loop, and an intracellular C-terminus. NMDA receptors (NMDARs) are formed from hetero-oligomeric assemblies of NR1 subunits with NR2 (A-D) and NR3A subunits, whereas AMPA receptors (AMPARs) are built from subunits GluR1-4 and KA receptors (KARs) are formed from subunits GluR5-7 and KA-1 and 2 [2,3,4].AMPARs are activated directly by glutamate binding, and their activation leads to changes in the membrane potential of the postsynaptic neuron. In contrast...

An EssentialDrosophilaGlutamate Receptor Subunit That Functions in Both Central Neuropil and Neuromuscular Junction

“…Because it is increasingly apparent that many aspects of glutamate receptor assembly and trafficking depend on the presence of specific receptor subunits (for review, see Barry and Ziff, 2002;Molnar and Isaac, 2002;Sheng and Hyoung Lee, 2003;van Zundert et al, 2004), a complete grasp of glutamate receptor composition is critical for studies of postsynaptic development and receptor regulation. The Drosophila NMJ is a genetically tractable glutamatergic synapse that is widely exploited for molecular studies of synaptic development, function, and plasticity.…”

Assembly and cell surface expression of KA‐2 subunit‐containing kainate receptors

“…While the roles of AMPA and NMDA receptors in mediating fast synaptic transmission and synaptic plasticity are relatively well understood (reviewed in Dingledine et al . 1999; Molnar and Isaac 2002), the molecular organization and physiological functions of KARs remains largely obscure. Like AMPA and NMDA receptors, KARs are also widely distributed throughout the CNS (Petralia et al .…”

Brain-Derived Neurotrophic Factor Controls Activity-Dependent Maturation of CA1 Synapses by Downregulating Tonic Activationof Presynaptic Kainate Receptors

“…However, acute inhibition of TrkB completely blocked the presynaptic changes, including decrease in frequency-dependent facilitation of EPSCs as well as loss of endogenous KAR activity, that are associated with LTP at immature synapses with initially low P r (Lauri et al, 2006). This suggests that, in young tissue, TrkB is not necessary for postsynaptic mechanisms underlying induction and early expression of pairing-induced synaptic potentiation, involving insertion and modified function of AMPA receptors at the postsynaptic density (Molnar and Isaac, 2002;Kerchner and Nicoll, 2008;Hanse et al, 2009). Rather, BDNF/TrkB appears critical for presynaptic plasticity at a stage of development when functional contact already exists but transmission is weak.…”

“…Neuronal activity is thought to either reinforce or weaken the nascent neuronal connections by using synaptic mechanisms similar to those regulating synaptic efficacy in the adult brain, namely long-term potentiation (LTP) and long-term depression (LTD), and thereby control selection of synaptic inputs to a given neuron. It is well established that Hebbian-type plasticity mechanisms can control the targeting and insertion of glutamate receptors to the postsynaptic density already at very early stages of synapse development (Molnar and Isaac, 2002;Collingridge et al, 2004;Kerchner and Nicoll, 2008;Hanse et al, 2009). However, the corresponding presynaptic processes controlling activity-dependent maturation of glutamate release machinery are less well characterized.…”