Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair

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2019Author
Casanovas i Llorens, Anna
Hernández, Sara
Santafé Martínez, Manel
Soto-Bernardini, María Clara
Schwab, Markus H.
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Salvany, Sara;
Casanovas i Llorens, Anna;
Tarabal Mostazo, Olga;
Piedrafita Llorens, Lídia;
Hernández, Sara;
Santafé Martínez, Manel;
...
Esquerda Colell, Josep.
(2019)
.
Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair.
FASEB Journal, 2019, vol. 33, num. 7, p. 7833-7851.
https://doi.org/10.1096/fj.201802329R.
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C-type synaptic boutons (C-boutons) provide cholinergic afferent input to spinal cord motor neurons
(MNs), which display an endoplasmic reticulum (ER)–related subsurface cistern (SSC) adjacent to their postsynaptic
membrane. A constellation of postsynaptic proteins is clustered at C-boutons, including M2 muscarinic receptors,
potassium channels, and s-1 receptors. In addition, we previously found that neuregulin (NRG)1 is associated with
C-boutons at postsynaptic SSCs, whereas its ErbB receptors are located in the presynaptic compartment. Cbouton–mediated regulation of MN excitability has been implicated in MN disease, but NRG1-mediated functions
and the impact of various pathologic conditions on C-bouton integrity have not been studied in detail. Here, we
investigated changes inC-boutons after electrical stimulation,pharmacological treatment, and peripheral nerve axotomy.
SSC-linked NRG1 clusters were severely disrupted in acutely stressedMNs and after tunicamycin-induced ER stress. In
axotomized MNs, C-bouton loss occurred in concomitance with microglial recruitment and was prevented by the ER
stress inhibitor salubrinal.Activatedmicroglia displayed apositive chemotaxis to C-boutons.Analysis of transgenicmice
overexpressing NRG1 type I and type III isoforms in MNs indicated that NRG1 type III acts as an organizer of SSC-like
structures, whereas NRG1 type I promotes synaptogenesis of presynaptic cholinergic terminals.Moreover,MN-derived
NRG1 signals may regulate the activity of perineuronal microglial cells. Together, these data provide new insights into
the molecular and cellular pathology of C-boutons in MN injury and suggest that distinct NRG1 isoform–mediated
signaling functions regulate the complex matching between pre- and postsynaptic C-bouton elements.