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.

谷氨酸失调发生在多发性硬化症 (MS) 中，但成熟少突胶质细胞的兴奋性毒性机制是否导致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，但仍会导致长期残疾，这凸显了神经保护的必要性。 MS 中出现 T2 可见白质病变之前，谷氨酸会升高。我们之前报道过，在实验性自身免疫性脑脊髓炎（EAE）中，髓磷脂反应性 T 细胞会刺激小胶质细胞从 x _c ^-转运蛋白系统中释放谷氨酸，从而促进髓磷脂降解。在这里，我们探索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少突胶质细胞体是由 AMPA 受体 (AMPAR) 介导的，AMPAR 亚基 GluA4 的基因缺失会降低细胞内钙反应。成熟少突胶质细胞上 GluA4 的诱导缺失可减弱 EAE，并且与无髓鞘轴突相比，有髓鞘轴突的损失选择性减少。这些数据将成熟少突胶质细胞中的 AMPAR 信号传导与有髓轴突的病理生理学联系起来，证明谷氨酸调节是多发性硬化症中潜在的神经保护策略。