Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes

Abstract

Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of presynaptic and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses.

Figure 1. AMPA receptor recruitment by select synaptic organizing complexes

Shown are interactions of trans-synaptic adhesion and other complexes with implications in AMPA receptor recruitment at excitatory synapses. A presynaptic SALM or SynDIG1 ligand has yet to be identified. Neurexin-Neuroligin-1 interaction requires synaptic activity (indicated by the long arrow) to affect GluA1-containing AMPA receptors through CaMKII, whereas other postsynaptic AMPA receptor mediators interact directly with GluA subunits or scaffolding proteins. Because of limited space, some complexes are shown in close proximity to or interacting with a single AMPA receptor-scaffold complex. This is not meant to imply a tertiary interaction.

Figure 2. Hypothetical time course of neurexin-induced synapse maturation

Presynaptic Neurexin interacts with Cbln1-GluD2 complex to induce synapse formation. Subsequent interaction of Neurexin with postsynaptic Neuroligin-1 might then lead to NMDA receptor recruitment at a nascent synapse while subsequent interaction of Neurexin with LRRTM2 might also lead to AMPA receptor recruitment. With time and activity, these mechanisms and others combine to form a stable, mature and active synapse replete with AMPA receptor trafficking and stabilizing machinery. Any given synapse might have one or any combination of the mechanisms shown, and the complement of trans-synaptic adhesion and AMPA receptor regulating machinery is likely to affect its potentiation capacity and strength of transmission at all points in the synapse’s lifetime.