Building and remodeling synapses

Abstract

Synaptic junctions are generated by adhesion proteins that bridge the synaptic cleft to firmly anchor pre- and postsynaptic membranes. Several cell adhesion molecule (CAM) families localize to synapses, but it is not yet completely understood how each synaptic CAM family contributes to synapse formation and/or structure, and whether or how smaller groups of CAMs serve as minimal, functionally cooperative adhesive units upon which structure is based. Synapse structure and function evolve over the course of development, and in mature animals, synapses are composed of a greater number of proteins, surrounded by a stabilizing extracellular matrix, and often contacted by astrocytic processes. Thus, in mature networks undergoing plasticity, persistent changes in synapse strength, morphology, or number must be accompanied by selective and regulated remodeling of the neuropil. Recent work indicates that regulated, extracellular proteolysis may be essential for this, and rather than simply acting permissively to enable synapse plasticity, is more likely playing a proactive role in driving coordinated synaptic structural and functional modifications that underlie persistent changes in network activity.

Figure 1

Schematic diagram illustrating examples of key synaptic CAM families. Shared domains are colored similarly. Postsynaptic membrane and associated proteins are shown at left, apposed to presynaptic membrane, at right. However, it should be noted that in some cases proteins shown on one side can be located on either pre- or postsynaptic sides (e.g. EphBs). For clarity, the majority of intracellular binding partners is not shown. Abbreviations are as indicated in the text.

Figure 2

Minimal adhesive unit. Diagram of a synapse shows hypothetical distribution of CAM interactions that are known to span synaptic clefts and could act coordinately. Molecule placement along the length of the cleft is based in part on published literature showing immunogold localization (e.g. (Buchert et al., 1999; Einheber et al., 1996; Elste and Benson, 2006; Fux et al., 2003; Petralia et al., 2005; Tremblay et al., 2007)) and unpublished data (Benson, Mortillo and Elste).

Figure 3

Extracellular proteolytic cascades drive synaptic structural and functional modifications locally in response to plasticity-inducing stimuli. Schematic diagram depicts a “resting synapse” (A) and subsequent changes to synapse structure/function following activity- and NMDA-receptor-induced activation of Neurotrypsin (B) or LTP- or learning-induced activation of MMP-9 (C). Neurotrypsin, which is released from presynaptic terminals upon activity (B), requires subsequent NMDA receptor activity by the postsynaptic neuron in order to cleave full-length Agrin, producing several cleavage fragments including bioactive Agrin-22. Agrin-22 then induces formation of dendritic filopodia through as-yet uncharacterized mechanisms. In contrast, MMP-9 is activated by LTP or inhibitory avoidance learning, where it signals through integrins to potentiate synaptic responses and enlarge dendritic spine heads, both of which require actin polymerization, as well as increase lateral mobility of NMDA receptors (C). See the text for further details of these and other proteolytic cascades, including relevant citations. Note however, that some of the molecular steps in these models are speculative.