Unitat de Neurobiologia Cellular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida-Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Lleida, Catalonia, Spain.
Unitat d'Histologia i Neurobiologia (UHN), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Catalonia, Spain.
FASEB J. 2019 Jul;33(7):7833-7851. doi: 10.1096/fj.201802329R. Epub 2019 Mar 26.
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 σ-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. C-bouton-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 in C-boutons after electrical stimulation, pharmacological treatment, and peripheral nerve axotomy. SSC-linked NRG1 clusters were severely disrupted in acutely stressed MNs 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. Activated microglia displayed a positive chemotaxis to C-boutons. Analysis of transgenic mice 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.-Salvany, S., Casanovas, A., Tarabal, O., Piedrafita, L., Hernández, S., Santafé, M., Soto-Bernardini, M. C., Calderó, J., Schwab, M. H., Esquerda, J. E. Localization and dynamic changes of neuregulin-1 at C-type synaptic boutons in association with motor neuron injury and repair.
C 型突触小泡（C-boutons）向脊髓运动神经元（MNs）提供胆碱能传入输入，MNs 显示与突触后膜相邻的内质网（ER）相关的基底池（SSC）。一系列突触后蛋白聚集在 C-boutons 处，包括 M2 毒蕈碱受体、钾通道和 σ-1 受体。此外，我们之前发现神经调节蛋白 1（NRG1）与突触后 SSC 处的 C-boutons 相关，而其 ErbB 受体位于突触前隔室。C-bouton 介导的 MN 兴奋性调节已被牵连到 MN 疾病中，但 NRG1 介导的功能以及各种病理条件对 C-bouton 完整性的影响尚未详细研究。在这里，我们研究了电刺激、药物处理和周围神经轴突切断后 C-boutons 的变化。急性应激 MNs 中 SSC 相关的 NRG1 簇严重破坏，在衣霉素诱导的 ER 应激后也是如此。在轴突切断的 MNs 中，C-bouton 丢失与小胶质细胞募集同时发生，并且 ER 应激抑制剂 salubrinal 可预防这种丢失。激活的小胶质细胞对 C-boutons 表现出正向趋化性。过表达 MN 中 NRG1 Ⅰ型和Ⅲ型异构体的转基因小鼠的分析表明，NRG1 Ⅲ型作为 SSC 样结构的组织者起作用，而 NRG1 Ⅰ型促进突触前胆碱能末梢的突触形成。此外，MN 衍生的 NRG1 信号可能调节神经周围小胶质细胞的活性。总的来说，这些数据为 MN 损伤中 C-boutons 的分子和细胞病理学提供了新的见解，并表明不同的 NRG1 异构体介导的信号功能调节了前突触和后突触 C-bouton 元件之间的复杂匹配。-萨尔瓦尼，S.，卡纳瓦斯，A.，塔拉巴尔，O.，皮德弗雷塔，L.，埃尔南德斯，S.，桑塔菲，M.，索托-贝尔纳迪尼，M.C.，卡尔德罗，J.，施瓦布，M.H.，埃斯奎塔，J.E. 神经调节蛋白 1 在 C 型突触小泡中的定位和动态变化与运动神经元损伤和修复有关。
