Synapses are sites where nerve impulses are transmitted from the axon of one neuron to the dendrite of an adjacent neuron, and the transformation of an initial axon–dendrite contact into a functional synapse requires the accumulation of the synaptic machinery at the contact site. This accumulation is mediated by intracellular organelles of trans-Golgi network (TGN) origin, but how are these organelles 'captured' and stabilized at neurite–neurite contact sites? New insights have now been provided by Schachner and colleagues in The Journal of Cell Biology.

In Drosophila, fasciclin II is important for synapse development, so the authors looked at the relationship between the distribution of the closest mammalian homologue of fasciclin II — neural cell adhesion molecule (NCAM) — and the localization of intracellular organelles in hippocampal neurons. They found that a subpopulation of organelles, which could be seen moving along neurites, were associated with clusters of cell-surface-localized NCAM.

Using organelle-specific markers, Schachner and co-workers showed that these NCAM clusters colocalize with markers of TGN organelles. In addition, they found that NCAM180 — which binds spectrin — is the NCAM isoform that interacts with TGN organelles. TGN organelles are lined with a spectrin cytoskeleton, and the authors showed that the interaction between cell-surface NCAM180 and TGN organelles is mediated by spectrin.

Cell-surface NCAM180 clusters and intracellular organelles were seen to move bidirectionally along neurites. However, within several minutes of neurite–neurite contact, the authors found that these mobile NCAM180 clusters and the associated organelles became 'trapped' at the contact site. So, is this 'trapping' relevant to synaptic differentiation?

Schachner and colleagues observed 29 cases of synaptic differentiation and found that 26 coincided with NCAM180 clusters. Only one of these 26 nascent synapses was unstable, compared with two of the three synapses that formed in the absence of NCAM180. These results indicate that NCAM is important for synaptic differentiation and stabilization.

The authors clarified the role of NCAM when they showed that organelles spend more time at neurite–neurite contact sites in wild-type neurons than in NCAM-deficient neurons, and that organelles leave contacts sites four times more often in NCAM-deficient neurons than in wild-type neurons. NCAM therefore functions to 'anchor' TGN organelles at contact sites.

The work of Schachner and colleagues has highlighted a new role for NCAM in anchoring TGN organelles at initial neurite–neurite contact sites during synapse development, and has shown for the first time that recognition molecules like NCAM can “...provide a direct link between extracellular cues and intracellular organelles to stabilize them at nascent synapses”.