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The electric activity of lower motor neurons (MNs) appears to play a role in determining cell-vulnerability in MN diseases. MN excitability is modulated by cholinergic inputs through C-type synaptic boutons, which display an endoplasmic reticulum-related subsurface cistern (SSC) adjacent to the postsynaptic membrane. Besides cholinergic molecules, a constellation of proteins involved in different signal-transduction pathways are clustered at C-type synaptic sites (M2 muscarinic receptors, Kv2.1 potassium channels, Ca2+ activated K+ [SK] channels, and sigma-1 receptors [S1R]), but their collective functional significance so far remains unknown. We have previously suggested that neuregulin-1 (NRG1)/ErbBs-based retrograde signalling occurs at this synapse. To better understand signalling through C-boutons, we performed an analysis of the distribution of C-bouton-associated signalling proteins. We show that within SSC, S1R, Kv2.1 and NRG1 are clustered in highly specific, non-overlapping, microdomains, whereas ErbB2 and ErbB4 are present in the adjacent presynaptic compartment. This organization may define highly ordered and spatially restricted sites for different signal-transduction pathways. SSC associated proteins are disrupted in axotomised MNs together with the activation of microglia, which display a positive chemotactism to C-bouton sites. This indicates that C-bouton associated molecules are also involved in neuroinflammatory signalling in diseased MNs, emerging as new potential therapeutic targets. We would like to thank Dr. Ronald W. Oppenheim for his critical reading of the manuscript and for helpful comments and suggestions. We would also like to thank Marta Hereu for her technical assistance, Lidia Delgado, Gema Marta Martínez and M. Yolanda Muela, from the Unitat de Criomicroscòpia Electrònica (Centres Científics i Tecnològics de la Universitat de Barcelona), for their technical support with ultrastructural immunolabelling, Daniel Cabezas for his help in some experiments, and the SCT animal facility of the Universitat de Lleida for mouse care and housing. This work was supported by grants from the Ministerio de Economía y Competitividad cofinanced by FEDER (SAF2015–70801-R to J.E.E. and J.C.), and from Jack Van den Hoek a la investigació de l’ELA - Fundació Miquel Valls (to J.E.E.).