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首页> 外文期刊>Science Advances >Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation
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Reduction of AMPA receptor activity on mature oligodendrocytes attenuates loss of myelinated axons in autoimmune neuroinflammation

机译：成熟少突卵细胞对AMPA受体活性的降低衰减自身免疫性神经炎症中的骨髓轴突的损失

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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.
机译：谷氨酸诱发剂量在多发性硬化症（MS）中发生，但成熟寡核细胞中的兴奋毒性机制是否有助于脱髓鞘和轴突损伤是未探斗的。虽然目前的治疗调节免疫系统，但随后突出了长期残疾，突出了神经保护的需求。在T2可见的白质病变出现在MS中，谷氨酸升高。我们以前报道，髓鞘反应性T细胞引发小胶质细胞从系统x C中释放谷氨酸盐？促进实验性自身免疫性脑脊髓炎（EAE）中促进髓鞘的转运蛋白。在这里，我们探讨成熟少突胶质细胞中谷氨酸的靶标。大多数谷氨酸刺激的钙流入Oligodendrocyte Somas是AMPA受体（AMPAR）介导的，并且AMPAR亚单位GLUA4的遗传缺失降低了细胞内钙应答。与未键合的轴突相比，选择性地减少了对成熟少突胶质细胞的Glua4对成熟寡核细胞的诱导缺失，并选择性地减少了骨髓轴突。这些数据链接成熟寡替粒细胞的AMPAR信号传导至髓鞘轴突的病理生理学，证明谷氨酸调节作为MS中的潜在神经保护策略。

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