The dynamic synapse: neuronal nexus for signaling.

There is not much that appears static in the neuronal synapse--an abundance of genetic, biochemical, pharmacological, electrophysiological, and microscopic information regarding this structure has revealed that the key to its role in mediating cell-to-cell communication in the central and peripheral nervous systems is its ever-changing nature. Yet we remain at a gross level of understanding how this complex architecture arises and how it is modulated. This week, Science presents a Special Issue that highlights recent insights in the development, organization, and plasticity of the dynamic synapse. Science's STKE delves deeper into some of the proposed molecular mechanisms that underlie synaptic plasticity. What becomes clear from this exploration is that we are at an early and exciting stage of understanding communication through this intercellular link at a detailed molecular level. Synaptic connections between neurons and target cells develop, mature, stabilize, and remodel, but the activity-dependent and -independent nature of these steps is somewhat disputed. In Science , Cohen-Cory explains how various model systems and methodologies have limited or expanded some of the contrary views on the relationships between synaptic activity, synapse development, and the plasticity that has long been implicated in learning and memory. The STKE Archive is rich in Perspectives discussing various aspects of activity-dependent changes in synaptic function. For example, Impey and Goodman discuss the mechanisms by which activity alters gene expression, Kosik and Krichevsky describe how RNA translation may be locally regulated by synaptic activity, and O'Donovan and Darnell highlight how alternative splicing can be regulated by synaptic activity. Fluorescent and real-time visualization techniques applied to hippocampal and cortical neurons have accelerated our understanding of neuron connectivity in central synapses, and Protocols by Dodt et al . and Polleux and Ghosh describing such contemporary procedures can also be found in the STKE Archive. Hippocampal neurons have provided the primary experimental paradigm for examining mammalian central synaptogenesis and function, and their manipulation has revealed that specific neurotransmitters and their cognate receptors are critical components of the synaptic signaling network. Differential expression in the mammalian brain of three different receptors for the neurotransmitter glutamate has triggered interest in determining whether their expression at the cell surface is a mechanism for regulating synaptic strength. Additional diversity in glutamate receptors is further achieved through RNA editing, which is described by in the STKE Perspective by Schmauss and Howe. The STKE Protocol by Grosshans et al . describes methods for analysis of glutamate receptor expression in organotypic hippocampal slices. The STKE Review by Contractor and Heinemann provides insight into glutamate receptor trafficking, focusing on the mobilization of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors from intracellular pools to synaptic and nonsynaptic sites in the postsynaptic neuronal membrane. A network of proteins that associate with glutamate receptors, including membrane, cytoskeletal, and PDZ domain-containing intracellular proteins, may underlie the dynamics of receptor recruitment, stabilization, and turnover in the synapse. An STKE Perspective by deSouza and Ziff discusses the recent finding that the postsynaptic density protein PSD-95 is reversibly palmitoylated, a modification that could influence AMPA signaling by restricting receptor localization to membrane lipid rafts. This follows an emerging theme of how protein lipidation and location can control the activity of signaling molecules at membranes (see also the STKE Perspective by Berthiaume). A Science Review by Sheng and Kim further delineates the protein-protein interacting network of central synapses and the multiple biochemical pathways (including the Ras to mitogen-activation protein kinase, the calcium-calmodulin kinase II, and the phosphatidylinositol 3-phosphate kinase pathways) associated with activated glutamate receptors. It is clear that a spatiotemporal understanding is now needed to elucidate how these components and pathways are integrated into dynamic synaptic circuits both in the developing and mature nervous system. Neurotransmitters that modulate synaptic activity are released to postsynaptic neurons through exocytosis of cargo-carrying synaptic vesicles from presynaptic neurons. The Science Review by Rettig and Neher explains that tremendous insights into the molecular machinery controlling this calcium-triggered event have been gleaned from studying neurosecretory cells. Synaptic vesicles are also recycled locally, and the slow and fast tracks of this process are described in a review by Galli amd Haucke. The response of neurons to neurotransmitters is also dynamic and can change during development. In their STKE Perspective, Kriegstein and Owens propose some caution when categorizing neurotransmitters as either excitatory or inhibitory as they discuss the surprising discovery that γ-aminobutyric acid (GABA) can elicit both responses in the developing mammalian brain. A growing array of synapse components and signaling pathways implicated in synapse dynamics begs the question of how these elements couple to each other and how they are linked to synaptic activity. There is likely no simple strategy behind how synaptic activity modulates synapse architecture and vice versa. These issues are not only at the forefront of neuronal synapse research, but now also confront those who study similar "synaptic" cell-cell interfaces in other biological systems (see the Science Viewpoint by Dustin and Colman that contrasts the neuronal and immunological synapses). Featured in this Focus Issue Related Resources at STKE