Putting Everything Together

Whereas enormous progress has been made in the functional identification of axonal guidance molecules, the study of synaptogenesis and synaptic cell adhesion remains far behind. The reason for the relatively slow progress in studying synaptic cell adhesion appears to be two-fold. First, the molecules involved in synaptic cell adhesion likely have less clear-cut functions, but act in ensembles which among others determine the strength of a synaptic contact and specify its properties. Second, assaying for the functions in synaptogenesis and synaptic cell adhesion is much less straightforward than assaying for molecules with a function in axonal guidance. Nevertheless, the principles outlined above provide general ideas for a molecular framework of synaptogenesis that is illustrated as a model with candidate molecules, as far as identified, in Figure 0.320.

Briefly, it seems almost certain that all molecules involved in synaptogenesis will be multifunctional, but no molecule will be a master regulator of all other molecules. Moreover, it seems likely that synaptogenesis is a complex process that involves signaling on both sides of the synapse-to-be. Thus we postulate that initial synapse formation is due to a transient and rather nonspecific contact that may be mediated by the combined action of multiple cell adhesion molecules, possibly including protocadherins and other cadherins21. Afterward, synapses are validated and stabilized by a large number of activity-dependent processes, including the action of neurexins/neuroligins. It is likely that this 'stabilization' involves more than one particular process, and several different types of subreactions. For this step, neurexins and neuroligins are the best candidates because deletions of a subset of neurexins do not abolish synapse formation, but dramatically alter synapse specification22, and because increases in synapse density that are induced in transfected neurons by expression of neuroligin 1 depend on activation of NMDA receptors (ref. 20; see Figure 0.3). The variability of neurexins and neuroligins produced by multiple genes and alternative spicing might contribute to

Figure 0.3. Model of the Role of Cell Adhesion Molecules in Synapse Formation and Maturation. The initial synaptic contact between neurons is proposed to involve multiple cell adhesion molecules, including SynCAM and cadherins, which might impart specificity on synaptic contacts. The resulting immature synapses are functional, but are stabilized by activity-dependent processes. The model suggests that neuroligin 1 mediates the activity-dependent stabilization of transient synaptic contacts, and depends on the simultaneous activation of NMDA receptors. In promoting activity-dependent synapse stabilization, postsynaptic neuroligin 1 likely transduces a ¿ra«s-synaptic signal triggered by binding of its extracellular esterase-like domain to presynaptic neurexins. For more details, see ref. 20.

Figure 0.3. Model of the Role of Cell Adhesion Molecules in Synapse Formation and Maturation. The initial synaptic contact between neurons is proposed to involve multiple cell adhesion molecules, including SynCAM and cadherins, which might impart specificity on synaptic contacts. The resulting immature synapses are functional, but are stabilized by activity-dependent processes. The model suggests that neuroligin 1 mediates the activity-dependent stabilization of transient synaptic contacts, and depends on the simultaneous activation of NMDA receptors. In promoting activity-dependent synapse stabilization, postsynaptic neuroligin 1 likely transduces a ¿ra«s-synaptic signal triggered by binding of its extracellular esterase-like domain to presynaptic neurexins. For more details, see ref. 20.

synapse specification23. However, it is also probable that neurexins and neuroligins are not the only molecules that act here; for example, ephrins and Eph receptors might have additional major roles (e.g., see ref. 24). Uncovering the roles of various candidate synaptic cell adhesion molecules will be a major challenge for years to come.

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