Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany
Author for correspondence (e-mail: melitta.schachner{at}zmnh.uni-hamburg.de)
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Summary |
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Key words: Synaptogenesis, TGN, Transport, NCAM
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Introduction |
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At the synapse, information is transferred when a chemical messenger is released from synaptic vesicles and activates receptors in the apposed dendritic postsynaptic domain. Neurons in the CNS can be subdivided on the basis of the type of neurotransmitter they use: glutamate or -aminobutyric acid (GABA). The glutamatergic and GABAergic neurons are called excitatory and inhibitory, respectively, in reference to the type of response they elicit in the postsynaptic membrane. Whereas glutamate causes depolarization of the neuron and generation of an action potential, GABA hyperpolarizes cells, reducing the probability of an action potential. Thus, glutamate receptors of the N-methyl-D-aspartate (NMDA) and
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) types are present at excitatory synapses; whereas GABA receptors are found exclusively at inhibitory synapses (Fig. 1) (for reviews, see Kittler and Moss, 2001
; Moss and Smart, 2001
; Sheng and Pak, 2000
). In the peripheral nervous system, another type of excitatory connection the neuromuscular junction (NMJ) links the axon of a motor neuron and a muscle cell. NMJs use acetylcholine as a neurotransmitter, which activates acetylcholine receptors in the postsynaptic membrane of the muscle cell (reviewed by Sanes and Lichtman, 1999
).
The formation of synapses in the CNS is a highly complex process that needs to be orchestrated with high temporal and spatial precision. Synapse formation is accompanied by accumulation of synaptic organelles and proteins at the tiny sites where axons and dendrites contact each other (Ahmari et al., 2000; Friedman et al., 2000
; Zhai et al., 2001
; Sytnyk et al., 2002
; Shapira et al., 2003
). The result is the transformation of the initial contacts between filopodia of axonal or dendritic growth cones into functional synapses. Here, we summarize current knowledge of how multiple synaptic precursor structures derived from the trans-Golgi network (TGN) transport synaptic proteins to sites of synaptic contact, where they are trapped and mature into a functional synaptic machinery.
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Transport vesicles mediating synaptic protein delivery |
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Another type of axonal synaptic precursor pool consists of vesicles that are 80 nm in diameter and characterized by a dense core appearance. These dense core vesicles contain the presynaptic multi-domain proteins Piccolo and Bassoon that participate in the formation of the cytoskeletal matrix at the active zone of mature synapses (reviewed by Dresbach et al., 2001). Other molecules contained in these dense core vesicles are: the synaptic plasma membrane SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins syntaxin and SNAP-25; RIM (Rab3-interacting molecule); Munc18 and Munc13, which are the mammalian homologs of the Caenorhabditis elegans proteins UNC-18 and UNC-13; and the cell adhesion molecule N-cadherin. Interestingly, dense core vesicles do not contain VAMP2, synaptophysin, synaptotagmin, or the perisynaptic GABA transporter GAT1 (Zhai et al., 2001
; Shapira et al., 2003
). Whether synaptophysin, which is also transported by pleiomorphic structures covered with a spectrin-containing cytoskeleton (Nakata et al., 1998
; Sytnyk et al., 2002
), is present in the VAMP-containing vesicles or vesicles that constitute another type of transport carrier remains to be determined. Another unresolved issue is the presence of spectrin at the surface of VAMP-containing or dense core vesicles. The pleiomorphic structures and dense core vesicles contain largely non-overlapping sets of synaptic proteins. However, some proteins, such as VDCC, are present in both types of vesicle, which finally accumulate at nascent synapses, where they have been detected at the ultrastructural level (Ahmari et al., 2000
).
Less well characterized is the assembly of postsynaptic structures, which contain mainly neurotransmitter receptors, non-ligand-triggered ion channels, transporters, pumps and associated scaffolding proteins. However, it is evident that Golgi-related structures are present in dendrites (Sytnyk et al., 2002; Horton and Ehlers, 2003
; Maletic-Savatic and Malinow, 1998
) and different types of membranous carrier also exist postsynaptically. For example, in cortical neurons, the NMDA and AMPA receptors are transported at different speeds towards the nascent excitatory synapse in largely non-overlapping carriers (Washbourne et al., 2002
). Vesicles transporting the NMDA receptors utilize the neuron-specific kinesin motor KIF17 (Setou et al., 2000
; Guillaud et al., 2003
), whereas molecular motors associated with other types of carrier remain to be determined. Proteins associated with NMDA receptors in mature synapses, such as the cytoskeleton-associated protein PSD95 (postsynaptic density protein 95; also known as SAP90), may be recruited to the synaptic contact from a diffuse cytoplasmic pool after contact establishment (Bresler et al., 2001
). PSD95 can also be dynamically recruited to the membranes by palmitoylation (El-Husseini et al., 2002
), and has also been seen in association with carriers that are transported along growing dendrites (Prange and Murphy, 2001
). However, more recent studies indicate that PSD95 moves in clusters distinct from those containing NMDA receptors (Washbourne et al., 2002
).
Several lines of evidence show that the carriers that deliver synaptic proteins probably originate from the TGN, which can produce large pleiomorphic structures up to several microns in diameter (Nakata et al., 1998; Toomre et al., 1999
; Toomre et al., 2000
; Polishchuk et al., 2000
; Stephens and Pepperkok, 2001
) that are similar to the carriers that deliver presynaptic (Ahmari et al., 2000
; Nakata et al., 1998
; Sytnyk et al., 2002
) and postsynaptic (Washbourne et al., 2002
) proteins. Some of these contain proteins characteristic of the TGN, such as TGN-38 (Nakata et al., 1998
). Moreover, some of those accumulating at sites of contact that eventually became synapses contain TGN-specific adaptor proteins, such as ß-COP and
-adaptin, a subunit of the AP-1 complex (Sytnyk et al., 2002
). These can be loaded with the styryl dyes FM1-43 or FM4-64 following prolonged exposure, which specifically labels the TGN- or Golgi-like structures (Maletic-Savatic and Malinow, 1998
; Maletic-Savatic et al., 1998
; Tarabal et al., 2001
; Sytnyk et al., 2002
). The ability to accumulate these FM dyes also shows that the structures are connected with endosomal compartments, where FM dyes reside transiently before being transferred to TGN-like structures. A connection between the TGN and recycling endosomes has also been described in non-neuronal cells (Mallard et al., 1998
; Clague, 1998
) and may be important for the later stages of synaptic vesicle generation from the plasma membrane that are believed to occur after fusion of TGN-derived structures with the membrane (reviewed by Hannah et al., 1999
).
TGN-derived structures probably also have a function in the formation of inhibitory synapses. Direct and indirect evidence supports the view that the GABAA receptor, in association with gephyrin, a cytoskeleton-associated linker protein, is transported in TGN-derived structures that contain the ATPase N-ethylmaleimide-sensitive factor (NSF), a chaperone that activates SNARE proteins (Kneussel, 2002).
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Recognition molecules and synapse formation |
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Recognition molecules accumulate at synapses during development, which suggests that they might be involved in synapse stabilization through their adhesive properties. These molecules include N-cadherin, which is initially associated with all types of synapse in cell culture but then becomes restricted to excitatory synapses (Benson and Tanaka, 1998). Protocadherin-
, a molecule related to classical cadherins, is also found in a subset of excitatory synapses (Phillips et al., 2003
). Recognition molecules of the immunoglobulin superfamily, such as synaptic cell adhesion molecule (SynCAM) (Biederer et al., 2002
), nectins (Mizoguchi et al., 2002
) and neural cell adhesion molecule (NCAM) (Schachner, 1977; Sytnyk et al., 2002
) are also present in synapses.
Work in Drosophila first gave direct evidence of the role of recognition molecules in the induction of synapse formation. The lack of the cell adhesion molecule fasciclin II leads to a loss of synapses that have transiently formed in early development (Schuster et al., 1996). Studies in heterogenotypic co-cultures of neurons lacking NCAM, the closest mammalian homologue of fasciclin II, and wild-type neurons indicate that the NCAM-deficient cells form fewer synapses (Dityatev et al., 2000
). Overexpression of SynCAM in non-neuronal cells induces formation of synapses on the transfected cells by axons of co-cultured neurons (Biederer et al., 2002
), whereas inhibition of nectin-based adhesion by an inhibitor of nectin-1, glycoprotein D, results in a decrease in synapse size and a concomitant increase in synapse number (Mizoguchi et al., 2002
). Integrins, a large family of cell-surface receptors for extracellular matrix recognition molecules, are also associated with synapses (Chan et al., 2003
) and have also been suggested to induce synapse formation. Application of antibodies that block integrin function reduced the number of synapses in the apical dendrites of CA1 pyramidal neurons in organotypic cultures (Nikonenko et al., 2003
). Yet other recognition molecules that are present in synapses and are involved in synapse formation are the neurexins and neuroligins (Dean et al., 2003
). Overexpression of neuroligin induced synapse formation on transfected non-neuronal cells (Scheiffele et al., 2000
) and on cultured hippocampal neurons (Dean et al., 2003
) by activation of its binding partner neurexin. The ephrin B and EphB tyrosine kinase receptor system has also been implicated in the development of excitatory synapses through phosphorylation of the cell-surface-exposed heparin sulphate proteoglycan syndecan (Ethell et al., 2001
) or interaction with the NMDA receptor (Dalva et al., 2000
).
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Recognition molecules signal transport carriers to immobilize at sites of initial contacts |
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In the squid giant axon, subaxolemmal cisternae form junctions with the axolemma. These exhibit filamentous granular bridging structures 3 nm in diameter (Metuzals et al., 1997
), which suggests that cytoskeletal elements are involved. In accordance with this idea, we found that the link between TGN-derived carriers and cell-surface NCAM180, the largest major isoform of NCAM, which has the longest cytoplasmic domain, depends on proteins associated with the membranes of the organelles, such as spectrin. Spectrin has also been implicated in accumulation of synaptic proteins and initiation of synaptic transmission in Drosophila (Featherstone et al., 2001
). The cytoplasmic surface of Golgi- and TGN-derived structures is lined with a spectrin-actin cytoskeleton meshwork (De Matteis and Morrow, 2000
; Lippincott-Schwartz, 1998
; Holleran and Holzbaur, 1998
). Spectrin is tightly colocalized with both TGN-derived structures and NCAM clusters, and mediates binding of the intracellular domain of NCAM180 to the organelles (Sytnyk et al., 2002
).
The association between NCAM and the organelles is tight enough to form a complex that moves along neurites before contact formation (Fig. 4). Time-lapse video recordings have shown that formation of contacts between filopodia of a neurite approaching its target neurite does not coincide with the localization of NCAM-organelle complexes. However, the complexes accumulate at the initial contact sites within minutes. NCAM clusters and organelles often pass the contact site several times, but finally one or even several of the pre-formed NCAM packets become `trapped' and remain at the site of contact for >1 hour. The period that contacts contain organelles is reduced 35% in NCAM-deficient neurons compared with wild-type neurons. Moreover, the organelles move away from the contact site
4 times more often in the NCAM-deficient neurons. NCAM thus seems to be important for stabilization of TGN-derived carriers at sites that ultimately become synapses (Sytnyk et al., 2002
).
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Transformation of initial contact complexes to synapses |
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TGN-derived carriers may also be important vehicles for delivery and release of secreted molecules such as signaling molecules of the Wnt family, which were discovered as morphogens but have recently been implicated in synaptogenesis (Hall et al., 2000; Packard et al., 2002
). Another class of secreted molecules that play a role in synapse organization is components of the extracellular matrix, including tenascin-C, tenascin-R and proteoglycans. Particularly striking in this respect are certain neurons surrounded by conspicuous extracellular matrix structures, called perineuronal nets, which envelop synapses formed on the cell bodies of these cells. Another example is the secreted neuronal-activity-regulated pentraxin (Narp), which induces clustering of AMPA receptors (reviewed by Dityatev and Schachner, 2003
). These secreted molecules can be delivered to the synapse by neurons (Horton and Ehlers, 2003
) or by synapse-associated glial cells, which appear to regulate synapse development by providing cholesterol and soluble and contact-dependent factors that support the structural stability of the synapses (reviewed by Pfrieger, 2002
). The targeting of intracellular organelles in glial cells towards nascent and functional synapses remains an intriguing possibility in synaptogenesis.
An important presynaptic step in synapse maturation is the segregation of synaptic plasma membrane proteins from synaptic-vesicle-associated proteins and the subsequent formation of synaptic vesicles and the presynaptic cytomatrix. Note that these proteins segregate into different transport carriers: synaptic-vesicle-associated integral membrane proteins (e.g. VAMP, SV2, synapsin and synaptophysin) are transported by the pleiomorphic tubulovesicular structures, whereas presynaptic plasma-membrane-associated proteins (e.g. syntaxin and SNAP-25) and cytomatrix proteins (Piccolo and Bassoon) are transported by dense core vesicles. Whether synaptic-vesicle-associated proteins and plasma-membrane-associated proteins are always segregated into different carrier systems remains to be determined, particularly given that other subpopulations of transport vesicles may exist. Postsynaptic transport carriers probably give rise to spine structures, including the spine apparatus, which are a reservoir of neurotransmitter receptors, recognition molecules, channels and pumps in mature synapses.
Neural recognition molecules, particularly NCAM, together with spectrin, are important not only for the initial accumulation of carriers at nascent synapses but also for synapse maturation at later stages of synapse development. During early stages of synapse stabilization, NCAM appears to be necessary both pre- and postsynaptically (Sytnyk et al., 2002), whereas at later stages synaptic strength depends predominantly on postsynaptically expressed NCAM in heterogenotypic co-cultures of hippocampal neurons (Dityatev et al., 2000
). A presynaptic role of NCAM is suggested by the observation that, at neuromuscular junctions of NCAM-deficient mice, synaptic clustering of Ca2+ channels and synaptic vesicles is reduced (Polo-Parada et al., 2001
). However, indirect postsynaptic effects from NCAM-positive muscle cells cannot be excluded. Interestingly, similar effects are seen in Drosophila lacking
- and ß-spectrin (Featherstone et al., 2001
). These findings suggest that NCAM and spectrin constitute a molecular clamp that holds the presynaptic machinery in apposition to the postsynaptic membrane by homo- or heterophilic interactions. Maturation of the synaptic machinery is severely impaired at the neuromuscular junctions of NCAM-deficient mice, which shows that NCAM is directly involved in this process (Polo-Parada et al., 2001
).
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Conclusions and perspectives |
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The observation that NCAM cooperates with spectrin to mediate accumulation of TGN-derived carriers at sites of cell-cell contact provides the first clue as to how the carriers accumulate at these sites with such remarkable precision and speed. It also begs the question of what other synaptic proteins these carriers transport (Fig. 2). Both pre- and postsynaptic transport carriers are tethered to NCAM clusters at the cell surface, which suggests that NCAM is involved in the accumulation and maturation of transport carriers both pre- and postsynaptically. The carriers associated with NCAM and their cargos remain to be characterized in detail.
The link between organelles and cell-surface NCAM180 involves proteins associated with the cytoplasmic side of the TGN-derived structures. Spectrin has been identified as one such link, being highly enriched in vesicular and tubular membranous compartments. The spectrin skeleton not only associates with NCAM (Sytnyk et al., 2002; Leshchyns'ka et al., 2003
) but also contributes to the maintenance of Golgi structures and the efficiency of protein trafficking in the early secretory pathway (reviewed by De Matteis and Morrow, 2000
). Whether other peripheral proteins of TGN membranes, such as adaptor proteins or additional components of the spectrin meshwork, provide links to cell-surface recognition molecules is an intriguing issue. Among the possible candidates is ankyrin, which interacts with spectrin and the neural cell adhesion molecules L1 and CHL1, both members of the immunoglobulin superfamily (reviewed by Bennett and Baines, 2001
). Whether cadherins (particularly protocadherins), integrins, members of the neuroligin and neurexin families, receptor tyrosine kinases of the Eph-receptor family and their cognate ephrin ligands are also involved in targeting of TGN-derived structures to synapses also remains to be established.
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Acknowledgments |
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Footnotes |
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References |
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Ahmari, S. E., Buchanan, J. and Smith, S. J. (2000). Assembly of presynaptic active zones from cytoplasmic transport packets. Nat. Neurosci. 3, 445-451.[CrossRef][Medline]
Bennett, V. and Baines, A. J. (2001). Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol. Rev. 81, 1353-1392.
Benson, D. L. and Tanaka, H. (1998). N-cadherin redistribution during synaptogenesis in hippocampal neurons. J. Neurosci. 18, 6892-6904.
Biederer, T., Sara, Y., Mozhayeva, M., Atasoy, D., Liu, X., Kavalali, E. T. and Südhof, T. C. (2002). SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297, 1525-1531.
Bradke, F. and Dotti, C. G. (1998). Membrane traffic in polarized neurons. Biochim. Biophys. Acta. 1404, 245-258.[Medline]
Bradke, F. and Dotti, C. G. (2000). Establishment of neuronal polarity: lessons from cultured hippocampal neurons. Curr. Opin. Neurobiol. 10, 574-581.[CrossRef][Medline]
Bresler, T., Ramati, Y., Zamorano, P. L., Zhai, R., Garner, C. C. and Ziv, N. E. (2001). The dynamics of SAP90/PSD-95 recruitment to new synaptic junctions. Mol. Cell. Neurosci. 18, 149-167.[CrossRef][Medline]
Chan, C. S., Weeber, E. J., Kurup, S., Sweatt, J. D. and Davis, R. L. (2003). Integrin requirement for hippocampal synaptic plasticity and spatial memory. J. Neurosci. 23, 7107-7116.
Choquet, D. and Triller, A. (2003). The role of receptor diffusion in the organization of the postsynaptic membrane. Nat. Rev. Neurosci. 4, 251-265.[CrossRef][Medline]
Clague, M. J. (1998). Molecular aspects of the endocytic pathway. Biochem. J. 336, 271-282.[Medline]
Dai, Z. and Peng, H. B. (1996). Dynamics of synaptic vesicles in cultured spinal cord neurons in relationship to synaptogenesis. Mol. Cell. Neurosci. 7, 443-452.[CrossRef][Medline]
Dalva, M. B., Takasu, M. A., Lin, M. Z., Shamah, S. M., Hu, L., Gale, N. W. and Greenberg, M. E. (2000). EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945-956.[Medline]
Dean, C., Scholl, F. G., Choih, J., DeMaria, S., Berger, J., Isacoff, E. and Scheiffele, P. (2003). Neurexin mediates the assembly of presynaptic terminals. Nat. Neurosci. 6, 708-716.[CrossRef][Medline]
De Matteis, M. A. and Morrow, J. S. (2000). Spectrin tethers and mesh in the biosynthetic pathway. J. Cell Sci. 113, 2331-2343.
Dresbach, T., Qualmann, B., Kessels, M. M., Garner, C. C. and Gundelfinger, E. D. (2001). The presynaptic cytomatrix of brain synapses. Cell Mol. Life Sci. 58, 94-116.[Medline]
Dityatev, A. and Schachner, M. (2003). Extracellular matrix molecules and synaptic plasticity. Nat. Rev. Neurosci. 4, 456-468.[CrossRef][Medline]
Dityatev, A., Dityateva, G. and Schachner, M. (2000). Synaptic strength as a function of post- versus presynaptic expression of the neural cell adhesion molecule NCAM. Neuron 26, 207-217.[Medline]
El-Husseini, Ael-D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R. A. and Bredt, D. S. (2002). Synaptic strength regulated by palmitate cycling on PSD-95. Cell 108, 849-863.[Medline]
Ethell, I. M., Irie, F., Kalo, M. S., Couchman, J. R., Pasquale, E. B. and Yamaguchi, Y. (2001). EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001-1013.[Medline]
Featherstone, D. E., Davis, W. S., Dubreuil, R. R. and Broadie, K. (2001). Drosophila - and ß-spectrin mutations disrupt presynaptic neurotransmitter release. J. Neurosci. 21, 4215-4224.
Friedman, H. V., Bresler, T., Garner, C. C. and Ziv, N. E. (2000). Assembly of new individual excitatory synapses: time course and temporal order of synaptic molecule recruitment. Neuron 27, 57-69.[Medline]
Guillaud, L., Setou, M. and Hirokawa, N. (2003). KIF17 dynamics and regulation of NR2B trafficking in hippocampal neurons. J. Neurosci. 23, 131-140.
Hall, A. C., Lucas, F. R. and Salinas, P. C. (2000). Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100, 525-535.[Medline]
Hannah, M. J., Schmidt, A. A. and Huttner, W. B. (1999). Synaptic vesicle biogenesis. Annu. Rev. Cell. Dev. Biol. 15, 733-798.[CrossRef][Medline]
Holleran, E. A. and Holzbaur, E. L. (1998). Speculating about spectrin: new insights into the Golgi-associated cytoskeleton. Trends Cell Biol. 8, 26-29.[CrossRef][Medline]
Horton, A. C. and Ehlers, M. D. (2003). Dual modes of endoplasmic reticulum-to-Golgi transport in dendrites revealed by live-cell imaging. J. Neurosci. 23, 6188-6199.
Huber, A. B., Kolodkin, A. L., Ginty, D. D. and Cloutier, J. F. (2003). Signaling at the growth cone: ligand-receptor complexes and the control of axon growth and guidance. Annu. Rev. Neurosci. 26, 509-563.[CrossRef][Medline]
Johnston, P. A., Cameron, P. L., Stukenbrok, H., Jahn, R., de Camilli, P. and Südhof, T. C. (1989). Synaptophysin is targeted to similar microvesicles in CHO and PC12 cells. EMBO J. 8, 2863-2872.[Abstract]
Kittler, J. T. and Moss, S. J. (2001). Neurotransmitter receptor trafficking and the regulation of synaptic strength. Traffic 2, 437-448.[CrossRef][Medline]
Kneussel, M. (2002). Dynamic regulation of GABAA receptors at synaptic sites. Brain Res. Brain Res. Rev. 39, 74-83.[Medline]
Kraszewski, K., Mundigl, O., Daniell, L., Verderio, C., Matteoli, M. and de Camilli, P. (1995). Synaptic vesicle dynamics in living cultured hippocampal neurons visualized with CY3-conjugated antibodies directed against the lumenal domain of synaptotagmin. J. Neurosci. 15, 4328-4342.[Abstract]
Leshchyns'ka, I., Sytnyk, V., Morrow, J. S. and Schachner, M. (2003). Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth. J. Cell Biol. 161, 625-639.
Lippincott-Schwartz, J. (1998). Cytoskeletal proteins and Golgi dynamics. Curr. Opin. Cell Biol. 10, 52-59.[CrossRef][Medline]
Lledo, P. M., Zhang, X., Südhof, T. C., Malenka, R. C. and Nicoll, R. A. (1998). Postsynaptic membrane fusion and long-term potentiation. Science 279, 399-403.
Maletic-Savatic, M. and Malinow, R. (1998). Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part I: trans-Golgi network-derived organelles undergo regulated exocytosis. J. Neurosci. 18, 6803-6813.
Maletic-Savatic, M., Koothan, T. and Malinow, R. (1998). Calcium-evoked dendritic exocytosis in cultured hippocampal neurons. Part II: mediation by calcium/calmodulin-dependent protein kinase II. J. Neurosci. 18, 6814-6821.
Mallard, F., Antony, C., Tenza, D., Salamero, J., Goud, B. and Johannes, L. (1998). Direct pathway from early/recycling endosomes to the Golgi apparatus revealed through the study of shiga toxin B-fragment transport. J. Cell Biol. 143, 973-990.
Matteoli, M., Takei, K., Perin, M. S., Südhof, T. C. and de Camilli, P. (1992). Exo-endocytotic recycling of synaptic vesicles in developing processes of cultured hippocampal neurons. J. Cell Biol. 117, 849-861.[Abstract]
Metuzals, J., Chang, D., Hammar, K. and Reese, T. S. (1997). Organization of the cortical endoplasmic reticulum in the squid giant axon. J. Neurocytol. 26, 529-539.[CrossRef][Medline]
Mizoguchi, A., Nakanishi, H., Kimura, K., Matsubara, K., Ozaki-Kuroda, K., Katata, T., Honda, T., Kiyohara, Y., Heo, K., Higashi, M. et al. (2002). Nectin: an adhesion molecule involved in formation of synapses. J. Cell Biol. 156, 555-565.
Moss, S. J. and Smart, T. G. (2001). Constructing inhibitory synapses. Nat. Rev. Neurosci. 2, 240-250.[CrossRef][Medline]
Nakata, T., Terada, S. and Hirokawa, N. (1998). Visualization of the dynamics of synaptic vesicle and plasma membrane proteins in living axons. J. Cell Biol. 140, 659-674.
Nikonenko, I., Toni, N., Moosmayer, M., Shigeri, Y., Muller, D. and Sargent Jones, L. (2003). Integrins are involved in synaptogenesis, cell spreading, and adhesion in the postnatal brain. Brain Res. Dev. Brain Res. 140, 185-194.[Medline]
Packard, M., Koo, E. S., Gorczyca, M., Sharpe, J., Cumberledge, S. and Budnik, V. (2002). The Drosophila Wnt, wingless, provides an essential signal for pre- and postsynaptic differentiation. Cell 111, 319-330.[Medline]
Pfrieger, F. W. (2002). Role of glia in synapse development. Curr. Opin. Neurobiol. 12, 486-490.[CrossRef][Medline]
Phillips, G. R., Tanaka, H., Frank, M., Elste, A., Fidler, L., Benson, D. L. and Colman, D. R. (2003). Gamma-protocadherins are targeted to subsets of synapses and intracellular organelles in neurons. J. Neurosci. 23, 5096-5104.
Polishchuk, R. S., Polishchuk, E. V., Marra, P., Alberti, S., Buccione, R., Luini, A. and Mironov, A. A. (2000). Correlative light-electron microscopy reveals the tubular-saccular ultrastructure of carriers operating between Golgi apparatus and plasma membrane. J. Cell Biol. 148, 45-58.
Polo-Parada, L., Bose, C. M. and Landmesser, L. T. (2001). Alterations in transmission, vesicle dynamics, and transmitter release machinery at NCAM-deficient neuromuscular junctions. Neuron 32, 815-828.[Medline]
Prange, O. and Murphy, T. H. (2001). Modular transport of postsynaptic density-95 clusters and association with stable spine precursors during early development of cortical neurons. J. Neurosci. 21, 9325-9333.
Rizo, J. and Südhof, T. C. (2002). Snares and Munc18 in synaptic vesicle fusion. Nat. Rev. Neurosci. 3, 641-653.[Medline]
Sanes, J. R. and Lichtman, J. W. (1999). Development of the vertebrate neuromuscular junction. Annu. Rev. Neurosci. 22, 389-442.[CrossRef][Medline]
Schachner, M. (1997). Neural recognition molecules and synaptic plasticity. Curr. Opin. Cell Biol. 9, 627-634.[CrossRef][Medline]
Scheiffele, P., Fan, J., Choih, J., Fetter, R. and Serafini, T. (2000). Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657-669.[Medline]
Schmidt, A., Hannah, M. J. and Huttner, W. B. (1997). Synaptic-like microvesicles of neuroendocrine cells originate from a novel compartment that is continuous with the plasma membrane and devoid of transferrin receptor. J. Cell Biol. 137, 445-458.
Schuster, C. M., Davis, G. W., Fetter, R. D. and Goodman, C. S. (1996). Genetic dissection of structural and functional components of synaptic plasticity. I. Fasciclin II controls synaptic stabilization and growth. Neuron 17, 641-654.[Medline]
Setou, M., Nakagawa, T., Seog, D. H. and Hirokawa, N. (2000). Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796-1802.
Shapira, M., Zhai, R. G., Dresbach, T., Bresler, T., Torres, V. I., Gundelfinger, E. D., Ziv, N. E. and Garner, C. C. (2003). Unitary assembly of presynaptic active zones from Piccolo-Bassoon transport vesicles. Neuron 38, 237-252.[Medline]
Sheng, M. and Pak, D. T. (2000). Ligand-gated ion channel interactions with cytoskeletal and signaling proteins. Annu. Rev. Physiol. 62, 755-778.[CrossRef][Medline]
Shi, S. H., Hayashi, Y., Petralia, R. S., Zaman, S. H., Wenthold, R. J., Svoboda, K. and Malinow, R. (1999). Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation. Science 284, 1811-1816.
Stephens, D. J. and Pepperkok, R. (2001). Illuminating the secretory pathway: when do we need vesicles? J. Cell Sci. 114, 1053-1059.
Südhof, T. C. (1995). The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375, 645-653.[CrossRef][Medline]
Sytnyk, V., Leshchyns'ka, I., Delling, M., Dityateva, G., Dityatev, A. and Schachner, M. (2002). Neural cell adhesion molecule promotes accumulation of TGN organelles at sites of neuron-to-neuron contacts. J. Cell Biol. 159, 649-661.
Tarabal, O., Caldero, J., Llado, J., Oppenheim, R. W. and Esquerda, J. E. (2001). Long-lasting aberrant tubulovesicular membrane inclusions accumulate in developing motoneurons after a sublethal excitotoxic insult: a possible model for neuronal pathology in neurodegenerative disease. J. Neurosci. 21, 8072-8081.
Toomre, D., Keller, P., White, J., Olivo, J. C. and Simons, K. (1999). Dual-colour visualization of trans-Golgi network to plasma membrane traffic along microtubules in living cells. J. Cell Sci. 112, 21-33.
Toomre, D., Steyer, J. A., Keller, P., Almers, W. and Simons, K. (2000). Fusion of constitutive membrane traffic with the cell surface observed by evanescent wave microscopy. J. Cell Biol. 149, 33-40.
Walsh, F. S. and Doherty, P. (1997). Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu. Rev. Cell Dev. Biol. 13, 425-456.[CrossRef][Medline]
Washbourne, P., Bennett, J. E. and McAllister, A. K. (2002). Rapid recruitment of NMDA receptor transport packets to nascent synapses. Nat. Neurosci. 5, 751-759.[Medline]
Zakharenko, S., Chang, S., O'Donoghue, M. and Popov, S. V. (1999). Neurotransmitter secretion along growing nerve processes: comparison with synaptic vesicle exocytosis. J. Cell Biol. 144, 507-518.
Zhai, R. G., Vardinon-Friedman, H., Cases-Langhoff, C., Becker, B., Gundelfinger, E. D., Ziv, N. E. and Garner, C. C. (2001). Assembling the presynaptic active zone: a characterization of an active one precursor vesicle. Neuron 29, 131-143.[Medline]