Glutamatergic synapses are arguably the best understood synapses in the mammalian CNS. There are many good reasons why much research has focused on this sub-population of synaptic junctions. Glutamatergic synapses represent the primary fast excitatory connections that link principal neurons in all brain areas into circuits. Glutamatergic synapses undergo profound changes in structure and function during development and in association with learning processes. Finally, altered glutamatergic function appears to be a central element for several brain disorders. The discovery of molecular mechanisms for synapse assembly and function has been greatly facilitated by the abundance of glutamatergic connections. Glutamatergic synapses likely outnumber all other types of chemical synapses in the brain. This abundance paved the way to the identification of the first synaptic components using biochemical isolation of synaptic vesicle proteins and components of the postsynaptic density. Twenty-one years after the cloning of the first glutamate receptor GluA1, and 18 years after the cloning of the first synaptic scaffolding protein PSD-95, we now have not only detailed insights into the composition of glutamatergic synaptic structures but also substantial insight into the molecular mechanisms underlying the formation, plasticity and function of glutamatergic synapses.
The goal of this Special Issue on ‘Glutamatergic Synapses’ is to discuss key advances in our current understanding of three broad themes of synaptic mechanisms, employing glutamatergic synapses as a showcase. This Special Issue covers: (i) mechanisms of synapse assembly; (ii) synaptic plasticity associated with learning; and (iii) the modification and alteration of glutamatergic synapses in disease states.
The articles by Umemori, Yuzaki, Washbourne and Boulanger explore different molecular trans-synaptic signals that contribute to the assembly of synaptic junctions. For both secreted growth factors and cell adhesion molecules, ‘synaptogenic’ activities have been identified that can drive a substantial degree of the synapse differentiation program. Multiple signals appear to act at a single synaptic site but there are also signals, such as Cbln1, that appear to exhibit unique functions at specific synaptic junctions in vivo.
Calcium transients have emerged as a central signaling mechanism during development, maturation and plasticity of glutamatergic synapses. Lohmann discusses synaptic calcium dynamics at incipient and maturing synapses, and their role in regulating the functional and morphological differentiation of synapses. Bito then explores in detail the functions of one key calcium effector – the calmodulin-dependent kinases. The theme of calcium signaling is further extended in the article by Kittler, who discusses recent insights into mitochondrial trafficking and calcium buffering at glutamatergic synapses.
Once formed, synaptic networks and synapses themselves exhibit substantial morphological and functional plasticity. Kasai formulates a set of ‘spine learning rules’ summarizing principles underlying the plasticity of dendritic spines. As the primary carrier of synaptic currents, AMPA-type glutamate receptors and their dynamics have long been at the center of attention in studies on postsynaptic glutamatergic function. While AMPA-receptors were initially viewed as tetrameric ion channels that are recruited and regulated through cytoplasmic scaffolding molecules, there has been a recent surge in the identification of transmembrane accessory proteins that have key functions in AMPA-receptor regulation. These rapidly developing areas started with the identification of TARPs and more recently lead to the identification of several novel AMPA-receptor associated proteins (Diaz). Another key insight, derived from imaging techniques that enable tracking of single AMPA-receptor complexes along the dendritic plasma membrane and within synapses, concerns the dynamic nature of postsynaptic complexes. Choquet provides a discussion of mechanisms that not only control the retention and density of AMPA-receptors in postsynaptic sites but also the activity-dependent regulation of AMPA-receptor trafficking and its relevance for fast synaptic transmission. Kiefer then explores the mechanisms of AMPA-receptor trafficking during learning. Her article also provides a link to the final topic area of this special review issue: glutamate receptor dynamics and their regulation in disease states. Articles by Salter, Beattie and Balice-Gordon exemplify how the recent knowledge gained in basic cell biological studies on AMPA-receptor trafficking provides crucial advances in understanding physiological and cognitive disease states, ranging from nociception to injury-induced cell death and mechanisms of synaptic encephalitis.
Research conducted during the past 20 years on glutamatergic synapses has yielded substantial advances in our understanding of synapse formation and plasticity in the CNS. Still, many challenges remain for the years to come. One major unresolved question concerns the molecular mechanisms underlying the life-cycle, and in particular the neurotransmitter specification of central synapses. For instance, although some trans-synaptic signaling systems are known to contribute to synapse assembly, targeted gene deletion studies in the CNS have not yet identified a single molecule that is indispensable for synapse formation or neurotransmitter specification, unlike the crucial role of the agrin-Lrp4-MuSK-rapsyn signaling cascade at the neuromuscular junction. This failure may have multiple reasons. It may indicate that the key signaling systems for most synaptic junctions remain to be identified. Alternatively, mutant analysis may need to be performed with higher resolution focusing on genetically identified cell populations or specific pairs of synaptically connected cells to facilitate identification of more significant mutant phenotypes in vivo. Finally, the existence of multiple signaling pathways operating in parallel in developing synapses might ensure functional redundancy. Considering their plastic nature, the functional requirements for central synapses may thus differ significantly from their cholinergic neuromuscular counterparts.
Looking forward, the wealth of information now available on glutamatergic synapses provides a useful roadmap for more intensely exploring molecular mechanisms at synapses using other neurotransmitters, such as central cholinergic, GABAergic, glycinergic, serotonergic and dopaminergic synapses. Formation and plasticity might employ conceptually common, molecularly overlapping mechanisms of synapse formation and plasticity. The increasing availability of markers and tools for cell type-specific intervention should now enable expanding studies of synapse formation and plasticity to these less characterized types of synapses in the near future. Discovery of these organizing principles will represent a major step for our understanding of the functional organization of the nervous system.