Synaptogenesis in the CNS: an odyssey from wiring together to firing together

Abstract

To acquire a better comprehension of nervous system function, it is imperative to understand how synapses are assembled during development and subsequently altered throughout life. Despite recent advances in the fields of neurodevelopment and synaptic plasticity, relatively little is known about the mechanisms that guide synapse formation in the central nervous system (CNS). Although many structural components of the synaptic machinery are pre-assembled prior to the arrival of growth cones at the site of their potential targets, innumerable changes, central to the proper wiring of the brain, must subsequently take place through contact-mediated cell-cell communications. Identification of such signalling molecules and a characterization of various events underlying synaptogenesis are pivotal to our understanding of how a brain cell completes its odyssey from "wiring together to firing together". Here we attempt to provide a comprehensive overview that pertains directly to the cellular and molecular mechanisms of selection, formation and refinement of synapses during the development of the CNS in both vertebrates and invertebrates.

Figure 1. Wiring together to firing together

A, as pre- and postsynaptic growth cones approach each other, transmitter-receptor interactions, via the release of presynaptic vesicles, attract appropriate target growth cones by binding to and stimulating postsynaptic receptors. Various components of the pre- and postsynaptic specializations, including presynaptic packets containing synaptic machinery and channels and postsynapatic proteins such as PSD-95 are mobile prior to contact. B, as the extending growth cones contact, the growth cones smoothe, and asymmetric interactions between membrane-bound molecules such as neurexins/neuroligins, cadherins, and integrins mark the synaptic site and stabilize pre- and postsynaptic scaffolding proteins such as CASK and PSD-95. C, subsequent maturation of the synaptic contact and interactions between trophic ligands and receptors leads to clustering of calcium channels and synaptic vesicles at the presynaptic terminal and transmitter receptors at the postsynaptic bouton.