CNS synapses are stabilized trans‐synaptically by laminins and laminin‐interacting proteins

Abstract

The retina expresses several laminins in the outer plexiform layer (OPL), where they may provide an extracellular scaffold for synapse stabilization. Mice with a targeted deletion of the laminin β2 gene (Lamb2) exhibit retinal disruptions: photoreceptor synapses in the OPL are disorganized and the retinal physiological response is attenuated. We hypothesize that laminins are required for proper trans-synaptic alignment. To test this, we compared the distribution, expression, association and modification of several pre- and post-synaptic elements in wild-type and Lamb2-null retinae. A potential laminin receptor, integrin α3, is at the presynaptic side of the wild-type OPL. Another potential laminin receptor, dystroglycan, is at the post-synaptic side of the wild-type OPL. Integrin α3 and dystroglycan can be co-immunoprecipitated with the laminin β2 chain, demonstrating that they may bind laminins. In the absence of the laminin β2 chain, the expression of many pre-synaptic components (bassoon, kinesin, among others) is relatively undisturbed although their spatial organization and anchoring to the membrane is disrupted. In contrast, in the Lamb2-null, β-dystroglycan (β-DG) expression is altered, co-localization of β-DG with dystrophin and the glutamate receptor mGluR6 is disrupted, and the post-synaptic bipolar cell components mGluR6 and GPR179 become dissociated, suggesting that laminins mediate scaffolding of post-synaptic components. In addition, although pikachurin remains associated with β-DG, pikachurin is no longer closely associated with mGluR6 or α-DG in the Lamb2-null. These data suggest that laminins act as links among pre- and post-synaptic laminin receptors and α-DG and pikachurin in the synaptic space to maintain proper trans-synaptic alignment.

Collective adhesion and displacement of retinal progenitor cells upon extracellular matrix substrates of transplantable biomaterials

“…The observed changes in the adhesive behavior of RPCs were evaluated in relation to expression of a panel of cell surface adhesion molecules known to serve as receptors for one or more of the ECM materials used as substrates in this study: integrin α3, integrin α7, integrin β3, and CD44. As noted in Table 4 , integrin α3 60 – 65 and integrin α7 66 – 69 bind to FN and LM, CD44 39, 75 – 78 is the receptor for HA, and integrin β3 70 – 74 is expressed by cells of the retinal pigment epithelium (RPE) and highly implicated in retinal angiogenesis. We observed that RPCs seeded onto substrates identified as ligands expressed somewhat higher levels of most receptors than when seeded onto PLL.…”

Microglia Mediate Synaptic Material Clearance at the Early Stage of Rats With Retinitis Pigmentosa

“…However, deletion of RIBEYE, which substantially decreases the number of ribbons in retinal synapses and disrupts neurotransmitter release, does not affect the overall organization and synaptic connectivity of the retina (49). The loss of the typical triad organization does not disturb the gross structure of bipolar dendritic tips, including mGluR6 accumulation (50–52). Together with findings from the present report, perturbations in synaptic inputs and integrity did not directly lead to mGluR6 elimination via degradation, suggesting that synapse loss might have resulted from phagocytosis by microglia cells.…”

Analysis of α-Dystroglycan/LG Domain Binding Modes: Investigating Protein Motifs That Regulate the Affinity of Isolated LG Domains

“…However, the KVR motif does not appear to be conserved in neurexins (Figure 10), thus other factors could be involved. The fine regulation of the affinities between DG and these neuronal proteins may make important contributions in the central nervous system for the stability of synaptic elements (Hunter et al, 2017) and/or for neuronal pathfinding (Wright et al, 2012).…”