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Review
. 2009 Oct;1(4):a003079.
doi: 10.1101/cshperspect.a003079.

Cell adhesion, the backbone of the synapse: "vertebrate" and "invertebrate" perspectives

Nikolaos Giagtzoglou  1 , Cindy V Ly, Hugo J Bellen
Affiliations
Review

Cell adhesion, the backbone of the synapse: "vertebrate" and "invertebrate" perspectives

Nikolaos Giagtzoglou et al. Cold Spring Harb Perspect Biol. 2009 Oct.

Abstract

Synapses are asymmetric intercellular junctions that mediate neuronal communication. The number, type, and connectivity patterns of synapses determine the formation, maintenance, and function of neural circuitries. The complexity and specificity of synaptogenesis relies upon modulation of adhesive properties, which regulate contact initiation, synapse formation, maturation, and functional plasticity. Disruption of adhesion may result in structural and functional imbalance that may lead to neurodevelopmental diseases, such as autism, or neurodegeneration, such as Alzheimer's disease. Therefore, understanding the roles of different adhesion protein families in synapse formation is crucial for unraveling the biology of neuronal circuit formation, as well as the pathogenesis of some brain disorders. The present review summarizes some of the knowledge that has been acquired in vertebrate and invertebrate genetic model organisms.

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Figures

Figure 1.
Figure 1.
(A–C) Different stages of synapse formation. (A) Target selection, (B) Synapse assembly, (C) Synapse maturation and stabilization. (D–F) The role of cell adhesion molecules in synapse formation is exemplified by the paradigm of N-cadherin and catenins in regulation of the morphology and strength of dendritic spine heads. (D) At an early stage the dendritic spines are elongated from motile structures “seeking” their synaptic partners. (E) The contacts between the presynaptic and postsynaptic compartments are stabilized by recruitment of additional cell adhesion molecules. Adhesional interactions activate downstream pathways that remodel the cytoskeleton and organize pre- and postsynaptic apparatuses. (F) Cell adhesion complexes, stabilized by increased synaptic activity, promote the expansion of the dendritic spine head and the maturation/ stabilization of the synapse. Retraction and expansion is dependent on synaptic plasticity.
Figure 2.
Figure 2.
Diagram of Nrx –Nlg, LRR, and Ig mediated adhesion at excitatory synapses. Neurexins participate in the organization of presynaptic apparatuses and are linked to the synaptic vesicle cycle through interaction with CASK/Mint/Veli. Neuroligins interact with the postsynaptic PDZ scaffolding molecule PSD-95, which organizes the postsynaptic receptors (mainly NMDAR). Neurexins and neuroligins also participate at inhibitory synapses. Therefore, they are important for the balance of excitatory and inhibitory neurotransmission. Postsynaptic NGL2 binds to presynaptic GPI anchored Netrin G. NGL2 binds to the postsynaptic PDZ scaffolding molecule PSD95 and recruits NMDAR, but not AMPAR, in coculture experiments. SALM family members regulate the differentiation of neurites, organize postsynaptic sites by interacting with PSD-95, and recruit mainly NMDAR, and to a lesser extend AMPAR, in coculture experiments. Although no effects of SALMs on presynaptic organization are known, SALMs form distinct homophilic and heterophilic interactions suggesting adhesive roles on both sides of synapses. Ig molecules participate in both the structural and the functional organization of the synapse. SynCAM forms preferentially heterophilic interactions and induces synapse formation in coculture experiments. Presynaptically, it participates in the functional organization of the terminal through the interaction with CASK/Mint/Veli complexes. Postsynaptically, it interacts with the scaffolding molecule PSD-95. NCAM and L1-CAM form homophilic complexes and regulate cytoskeleton dynamics pre- and postsynaptically through interactions with spectrin and ankyrin.
Figure 3.
Figure 3.
Diagram of LAR-liprin-α signaling and cadherin-nectin mediated adhesion at excitatory synapses. Liprin-α is the mediator of LAR signaling in both pre- and postsynaptic compartments. Thus, LAR/liprin-α complexes control neurotransmitter release and active zone formation through interactions with CAS/Mint/Veli, RIM, and ERC. LAR/liprin-α complexes regulate the postsynaptic organization of neurotransmitter receptors through interaction with GRIP, an AMPAR interacting protein. Cadherins are localized at puncta adherentia, the region flanking the active zone, along with nectins. Cadherins form homophilic complexes. The intracellular domain of cadherins interacts with catenins that ultimately link cadherins to the cytoskeleton. Cadherins are the physical link between synaptic activity and dendritic spine morphology (see text and Fig. 1C–F). Cadherins also control the organization of postsynaptic receptors. Nectins form heterophilic complexes and are able to recruit cadherins, but they can also interact with other adhesions systems, such as ephrins. Nectins are indirectly linked to the cytoskeleton through Afadin.
Figure 4.
Figure 4.
Synaptic wiring in the visual system of Drosophila. The compound eye of Drosophila is comprised of 750 ommatidia, each of which has eight photoreceptors, named R1–R8. Light stimulates the photoreceptors at the outer level of the retina, where the cell bodies lie. The signal is transmitted to the postsynaptic partners at the inner neuropils of the lamina and the medulla. R1–R6 photoreceptor axons from each ommatidium stop at the lamina, where they defasciculate and innervate nearby synaptic cartridges according to the principle of neural superposition. R7 and R8 photoreceptor axons continue to the medulla, where they terminate at distinct layers. In loss of function of N-cadherin, R1 and R6 fail to defasciculate, whereas R7 retracts to the wrong R8 specific layer. In loss of function of Flamingo cadherin, R1–R6 defasciculate but innervate abberrantly the synaptic cartridges, whereas the R8 photoreceptor axons terminate in the R7 layer (see text and also Mast et al. 2006; Ting and Lee 2007).
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