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. Keywordssynapse; proteinase; cell adhesion molecule; synaptic cleft; extracellular matrix; MMP; CAM Synapse adhesive structureAt CNS synapses, presynaptic terminals are bound to postsynaptic sites by a trans-synaptic adhesive apparatus that spans the intervening cleft. The synaptic cleft is defined by rigidly parallel membranes separated by 15-25 nm, and despite its name, is filled with proteins. High-resolution, ultrastructural techniques have revealed the presence of two sets of filaments within synaptic clefts. The first range between 4 -6 nm and bridge the cleft (Ichimura and Hashimoto, 1988;Landis and Reese, 1983). These filaments are sparsely but evenly distributed and undoubtedly contribute mechanically to junction adhesion. Consistent with this interpretation, recent work employing a cryo-EM technique that circumvents fixation and staining entirely reveals regularly distributed clusters spanning the cleft about 8.5 nm apart (Zuber et al., 2005). The second population of filaments that have been identified runs parallel to the apposing membranes (Ichimura and Hashimoto, 1988;Lucic et al., 2005). Proteins that are enriched in this zone can be stained with EPTA or bismuth iodide (Bloom and Aghajanian, 1968;Pfenninger, 1971a;Pfenninger, 1971b), suggesting that they are rich in basic residues, but the identities of the proteins comprising either bridging or parallel filaments are unknown.

Structural Components of Synaptic Plasticity and Memory Consolidation

“…In addition to active zone proteins, DCVs also transport CAMs (Zhai et al 2001). CAMs provide bidirectional signaling and coordinated recruitment of preand postsynaptic proteins and receptors Sytnyk et al 2002;Li and Sheng 2003;Scheiffele 2003;Ziv and Garner 2004;Waites et al 2005;Akins and Biederer 2006;Benson and Huntley 2010). DCVs contain cadherins (Zhai et al 2001), which cluster at the edges of synapses (Fannon and Colman 1996;Uchida et al 1996;Elste and Benson 2006), regulate AMPAR trafficking (Zhai et al 2001;Nuriya and Huganir 2006;Saglietti et al 2007), and contribute to the stabilization of enhanced synaptic efficacy during LTP (Bozdagi et al , 2010Tanaka et al 2000;Mendez et al 2010).…”

Dileucine and PDZ-binding Motifs Mediate Synaptic Adhesion-like Molecule 1 (SALM1) Trafficking in Hippocampal Neurons

“…2 are membrane-anchored molecules that directly interact through their extracellular domains to hold the membranes of two neurons together, at synapses or other points of contact (1)(2)(3)(4). SALMs, also known as Lrfn (leucine-rich repeat and fibronectin III domain-containing), are a recently identified family of adhesion molecules that are largely, but not exclusively, restricted to neurons (5)(6)(7)(8).…”

Very long-term memories may be stored in the pattern of holes in the perineuronal net

“…The only experimental test proposed was that disruption of the ECM would interfere with memory, for which there is (and already was) much evidence (6,12,(14)(15)(16), but the evidence is not incisive enough to be convincing. Meanwhile, reviews on MMPs in synaptic plasticity and learning conclude that the key substrates and downstream mechanisms remain unclear (7,16,26). In this article, I propose experiments to test this hypothesis and try to detail how they will improve on those hypotheses in the literature.…”