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...