Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation
Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation
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DOI：
10.1126/sciadv.aax5936
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发表时间：
2020-01-01
期刊：
影响因子：
13.6
通讯作者：
DeSilva, Tara M.
中科院分区：
文献类型：
--
作者：
Evonuk, Kirsten S.;Doyle, Ryan E.;DeSilva, Tara M.
多发性硬化症(MS)会发生谷氨酸失衡，但成熟少突胶质细胞的兴奋毒性机制是否有助于脱髓鞘和轴突损伤尚不清楚。尽管目前的治疗方法可以调节免疫系统，但长期的残疾随之而来，突显了神经保护的必要性。在实验性自身免疫性脑脊髓炎(EAE)中，谷氨酸在T2可见白质损害出现之前就升高了。我们以前报道过，髓鞘反应性T细胞刺激小胶质细胞从系统x(C)(-)释放谷氨酸，促进髓鞘降解。在这里，我们探索在成熟的少突胶质细胞中谷氨酸的靶点。谷氨酸刺激的钙内流大多是AMPAR(AMPAR)介导的，AMPAR亚单位GluA4的基因缺失降低了细胞内钙反应。与无髓鞘轴突相比，成熟少突胶质细胞上可诱导的GluA4缺失可减弱EAE，并选择性地减少有髓轴突的丢失。这些数据将成熟少突胶质细胞中的AMPAR信号与有髓轴突的病理生理联系起来，表明谷氨酸调节是MS潜在的神经保护策略。
Glutamate dysregulation occurs in multiple sclerosis (MS), but whether excitotoxic mechanisms in mature oligodendrocytes contribute to demyelination and axonal injury is unexplored. Although current treatments modulate the immune system, long-term disability ensues, highlighting the need for neuroprotection. Glutamate is elevated before T2-visible white matter lesions appear in MS. We previously reported that myelin-reactive T cells provoke microglia to release glutamate from the system x(c)(-) transporter promoting myelin degradation in experimental autoimmune encephalomyelitis (EAE). Here, we explore the target for glutamate in mature oligodendrocytes. Most glutamate-stimulated calcium influx into oligodendrocyte somas is AMPA receptor (AMPAR)-mediated, and genetic deletion of AMPAR subunit GluA4 decreased intracellular calcium responses. Inducible deletion of GluA4 on mature oligodendrocytes attenuated EAE and loss of myelinated axons was selectively reduced compared to unmyelinated axons. These data link AMPAR signaling in mature oligodendrocytes to the pathophysiology of myelinated axons, demonstrating glutamate regulation as a potential neuroprotective strategy in MS.