Presynaptic terminals (red) form in nonneuronal cells expressing SynCAM.


Learning, memory, forgetting—these are functions of synapses, the connections between nerve cells. Although studies of nerve cell differentiation, migration, and axonal pathfinding have put neurons in the right neighborhood, considerable work is needed to understand the smaller scale problems of choosing an axon partner and forming a synapse.

Synapse formation requires SynCAM, according to Thomas Biederer, Thomas Südhof, and colleagues (University of Texas Southwestern Medical Center, Dallas, TX), who found that SynCAM mediated cell adhesion and initiated synapse differentiation. Expression of SynCAM in nonneuronal cells both induced neighboring neurons to form functional presynaptic terminals and, if glutamate receptors were added to the mix, induced postsynaptic membranes capable of electrical responses to glutamate. According to Biederer, the widely expressed SynCAM is one of four closely related proteins that may initiate synapse formation throughout the central nervous system.

With SynCAM so widely expressed at many synapses, the brain needs an additional method to order neurons into an organized pattern. This process of synaptic partner choice is addressed by Masahito Yamagata, Joshua Weiner, and Joshua Sanes (Washington University, Saint Louis, MO). They chose retinal ganglion cells (RGCs) to study synaptic specificity because axons of RGCs restrict themselves to specific layers within neuronal tissue, forming easily identifiable parallel lines of synapses.

They then looked for proteins that marked one RGC subset as different from another and found two adhesion proteins, sidekick (sdk)-1 and sdk-2. Sdks were concentrated at synapses and mediated adhesion only with other cells expressing the same sdk. Each sdk was found in nonoverlapping sets of cells, and ectopic expression redirected RGC axons toward inappropriate layers. Not every synaptic layer contained a sdk isoform, indicating that other proteins also mediate specificity. Both SynCAM and sdks are transmembrane immunoglobulin domain proteins with intracellular PDZ protein-binding motifs. Determining which PDZ domain proteins interact with SynCAM or sdk will be one next step toward determining the mechanics of synapse assembly. ▪


Biederer, E., et al.

Yamagata, M., et al.