Genetics and cell biology of building specific synaptic connectivity

Abstract

The assembly of specific synaptic connections during development of the nervous system represents a remarkable example of cellular recognition and differentiation. Neurons employ several different cellular signaling strategies to solve this puzzle, which successively limit unwanted interactions and reduce the number of direct recognition events that are required to result in a specific connectivity pattern. Specificity mechanisms include the action of contact-mediated and long-range signals that support or inhibit synapse formation, which can take place directly between synaptic partners or with transient partners and transient cell populations. The molecular signals that drive the synaptic differentiation process at individual synapses in the central nervous system are similarly diverse and act through multiple, parallel differentiation pathways. This molecular complexity balances the need for central circuits to be assembled with high accuracy during development while retaining plasticity for local and dynamic regulation.

Figure 1

Model mechanisms for synaptic specificity during development. Interactions with appropriate synaptic partners can be accomplished by mutual attraction through positive regulators (green), or selective repulsion through negative regulators (red) derived from an inappropriate target cell or released by other cell types in the target territory in the form of a morphogenetic gradient. The synapse formation competence of afferents can be locally controlled by priming factors that are released in the target territory. During development, synaptic specificity can emerge through the elimination of contacts with inappropriate targets. The formation of transient synapses with guidepost cells (squares) provide a means of prepatterning synaptic structures before final target cells have arrived or matured in the target area. In some systems, guidepost cells are transient populations that are eliminated by cell death once the final wiring pattern has been accomplished.

Figure 2

Synapse organizing signals. Differentiation of pre- and postsynaptic domains, recruitment of synaptic vesicles, and pre- and postsynaptic receptors and scaffolds can be driven by multiple trans-synaptic signals, derived from either a synaptic partner or astroglia that flank synaptic sites.