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First published online December 31, 2003
doi: 10.1242/10.1242/jcs.00956

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Trans-Golgi network delivery of synaptic proteins in synaptogenesis

Vladimir Sytnyk^*, Iryna Leshchyns'ka^*, Alexander Dityatev and Melitta Schachner

Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, D-20246 Hamburg, Germany

View larger version (42K): [in a new window]   Fig. 1. Organization of mature synapses in the CNS. (A) Hippocampal neurons maintained in culture for 12 days were labeled with antibodies against cytoskeleton-associated proteins MAP2 (green), a marker of dendrites, and tau (red), a marker of axons. Antibodies against synaptic vesicle protein synaptophysin (blue) were used to label presynaptic boutons. Axons form multiple synaptic contacts with the dendrites and cell body (soma) of the neuron (arrows). (B) Hippocampal neurons maintained in culture for 12 days were stained with antibodies against synaptophysin (green) to label axonal terminals, and NMDA (blue) and AMPA (red) receptors to label excitatory postsynaptic specializations. Arrows show examples of excitatory synapses where synaptophysin-labeled presynaptic boutons are apposed to accumulations of AMPA and/or NMDA receptors. Intracellular accumulations of NMDA and AMPA receptors are also seen (arrowhead). Bar, 10 µm (A and B). (C) Organization of excitatory and inhibitory synapses in the CNS. For more details, see the text.

View larger version (40K): [in a new window]   Fig. 2. Synaptic precursor organelles and cargo proteins. Presynaptically (upper part), at least two different types of synaptic precursor organelles are described. Pleiomorphic tubulovesicular organelles transport VAMP, voltage-dependent Ca2+ channel (VDCC), synaptic vesicle protein 2 (SV2), synapsin and amphiphysin. Another type of vesicle is characterized by its dense core and round appearance. These vesicles contain the presynaptic cytomatrix proteins Piccolo, Bassoon, the SNARE proteins syntaxin and SNAP-25, Rab3a/c and Rab3-interacting molecule (RIM), Munc18, Munc13, N-cadherin and VDCC. Synaptophysin is transported by pleiomorphic structures that are covered with spectrin-containing cytoskeleton. Whether these organelles belong to the same type as VAMP-containing vesicles or constitute another type remains to be determined. Postsynaptically (lower part), organelles containing NMDA and AMPA receptors constitute two different types of transport carriers. PSD95 is depicted in a diffuse pool, but also in association with vesicular structures that are distinct from NMDA and AMPA receptor-containing vesicles. It remains to be elucidated whether vesicular transport organelles contain NCAM pre- and postsynaptically.

View larger version (32K): [in a new window]   Fig. 3. Diagram of NCAM-mediated accumulation of TGN organelles at sites of contact followed by synaptic differentiation. TGN-derived carriers (gray) are bound to clusters of NCAM (red) by the plasma membrane-cytoskeleton linker protein spectrin (blue). Initially, the contact site does not contain NCAM-tethered organelles, but then captures NCAM-associated TGN organelles through NCAM-mediated interactions at the contact site. Next, TGN organelles further accumulate at stabilized contacts. Finally, the contact is transformed into a functional synapse where presynaptic transport carriers give rise to synaptic vesicles (green) and postsynaptic carriers are transformed into postsynaptic density components (black). In the mature synapse, spectrin is a prominent component of the postsynaptic membrane. Spectrin isoforms have also been detected, although less prominently, in the presynaptic compartment. Figure reproduced with permission from The Rockefeller University Press (Sytnyk et al., 2002).

View larger version (81K): [in a new window]   Fig. 4. Accumulation of NCAM-immunoreactive clusters and associated organelles at the contact site between two neurites. Live hippocampal neurons maintained for three days in culture were labeled with monoclonal NCAM antibodies (red). Intracellular organelles were loaded with FM1-43 applied for 24 hours before the start of recording (green). At the start of recording (0 seconds), the growth cones in the lower right hand corner (arrow) approach the diagonally oriented neurite. NCAM-immunoreactive clusters associated with intracellular organelles marked with FM1-43 and seen in yellow (marked by 1-4) move along the target neurite. During the recording time, three contacts are formed. At the end of the recording (330 seconds), each contact is associated with an NCAM-immunoreactive cluster and intracellular organelles on the target neurite. Bar, 10 µm for all frames. Figure reproduced with permission from The Rockefeller University Press (Sytnyk et al., 2002).

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