The findings discussed in this chapter suggest that ECM molecule may shape synaptogenesis via several mechanisms. On the one hand, they may aggregate and serve as scaffolds for accumulation of presynaptic Ca2+ channels, postsynaptic glutamate receptors and growth factors (Figure 11.3).

Figure 11.3. Hypothetical Mechanisms by which ECM Molecules Shape Synaptogenesis. Neuronal pentraxins, NP1 and NP2, may form scaffolds in the extracellular space, thus promoting clustering of postsynaptic AMPA subtype of glutamate (Glu) receptors (AMPARs) and associated proteins, such as Stargazin, PSD-95, and NMDA receptors (NMDARs). Scaffold-containing laminins cluster presynaptic voltage-dependent Ca2+ channels (VDCC). Similarly, heparan sulfate proteoglycans (HSPGs) in association with NCAM serve to accumulate FGF and amplify signaling via FGF receptors. Reelin and laminin may bind to their cell surface receptors (ApoER2 and integrins) and trigger intracellular cascades resulting in activation of tyrosine kinases of the Src family and tyrosine phosphorylation of effectors, including NMDA receptors (NMDAR).

Data on laminin and neuronal pentraxins spectacularly illustrate this mechanism. Additionally, a recent study on synaptogenic activity of the neural cell adhesion molecule NCAM shows that it is related to formation of a complex between polysialylated NCAM and heparan sulfate proteoglycans and signaling via fibroblast growth factor receptor (see Chapter 6). On the other hand, ECM

Presynaptic bouton

Presynaptic bouton

Postsynaptic dendrite

molecules may serve as ligands capable of activating intracellular signaling cascades via binding to cell surface receptors. A common feature of these signaling events is tyrosine phosphorylation of effectors involved in synaptic transmission and plasticity.

The ECM molecules and receptors mentioned above are by no means the only ones involved in synapse formation and function. An increasing number of ECM signals are now being implicated in these processes such as aggrecan, neurocan, brevican, versican and HB-GAM (see ref. 100 for review). In addition, ECM components such as F-spondin may modify protease function and lead to altering processing and breakdown of neuronal proteins implicated in synapse formation and function, such as amyloid precursor protein100,101. Thus, it is becoming clear that ECM may play a role in synaptogensis by modifying the adhesion of neuronal synaptogenic proteins, diffusional parameters of the extracellular space102, the response of neurons to growth factors73, and the synaptogenic state of neurons. How ECM does this and what receptors and signaling pathways are involved are questions still mostly waiting for answers.*

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