Abstract
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.
Highlights
Skeletal muscle contractions mediating motor behaviour involves the coordinated activity of distinct brain stem and spinal cord motor neuron (MN) populations
When the proportion of distinct types of presynaptic terminals contacted by microglial profiles was measured in MN somata 7 days after axotomy (Fig. 9d–g), we found that more than 50% of Vesicular acetylcholine transporter (VAChT)-positive or Vesicular glutamate transporter 1 (VGluT1)-positive terminals were intimately associated with microglial processes, whereas a much lower proportion of microglial profiles were in contact with GABAergic or serotoninergic synapses (Fig. 9h); data concerning the relative density of the distinct types of afferents do not account for these differences
We extend our previous report showing that the NRG1-ErbB2/3 signalling module is expressed at C-boutons[18], by providing a more detailed analysis of the compartmentation of these molecules and their relation with other proteins that are known to be clustered at this synaptic site
Summary
Skeletal muscle contractions mediating motor behaviour involves the coordinated activity of distinct brain stem and spinal cord motor neuron (MN) populations. G. locomotion), the highly organized pattern of MN activity is modulated by cholinergic inputs[1] These are delivered through C-type synaptic boutons originating from spinal interneurons. In a study examining the expression of NRG1 in phrenic spinal cord MNs, it was reported that this trophic protein is expressed in most cholinergic nerve terminals[17]; its precise subcellular localization was not addressed by these investigators. At C-type synaptic sites, in addition to the presence of cholinergic molecules, a constellation of proteins involved in different signal-transduction pathways are clustered, their functional significance remains largely unknown. In order to better understand synaptic signalling though C-boutons, we undertook a structural analysis of the spatial organization of distinct C-bouton-associated signalling proteins, and especially the NRG1-ErbBs module, in different MN populations. We examined changes in NRG1-ErbB expression during development and following peripheral nerve injury
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