Shanghai Mental Health Center, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health.
J Clin Invest. 2022 Apr 15;132(8). doi: 10.1172/JCI152187.
Proper myelination of axons is crucial for normal sensory, motor, and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive disorder (MDD), but the molecular mechanisms connecting demyelination with the pathobiology remain largely unknown. We observed demyelination and synaptic deficits in mice exposed to either chronic, unpredictable mild stress (CUMS) or LPS, 2 paradigms for inducing depression-like states. Pharmacological restoration of myelination normalized both synaptic deficits and depression-related behaviors. Furthermore, we found increased ephrin A4 receptor (EphA4) expression in the excitatory neurons of mice subjected to CUMS, and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviors. These animal data are consistent with the decrease in myelin basic protein and the increase in EphA4 levels we observed in postmortem brain samples from patients with MDD. Our results provide insights into the etiology of depressive symptoms in some patients and suggest that inhibition of EphA4 or the promotion of myelination could be a promising strategy for treating depression.
轴突的正常髓鞘形成对于正常的感觉、运动和认知功能至关重要。脱髓鞘可见于大脑疾病，如重度抑郁症（MDD），但脱髓鞘与病理生物学相关的分子机制在很大程度上仍不清楚。我们观察到，在经历慢性、不可预测的轻度应激（CUMS）或 LPS 的小鼠中出现脱髓鞘和突触缺陷，这两种模型可用于诱导类似抑郁的状态。髓鞘修复药物可使突触缺陷和与抑郁相关的行为正常化。此外，我们发现，在经历 CUMS 的小鼠的兴奋性神经元中，ephrin A4 受体（EphA4）表达增加，而 EphA4 的 shRNA 敲低可防止脱髓鞘和类似抑郁的行为。这些动物数据与我们在 MDD 患者的死后脑组织样本中观察到的髓鞘碱性蛋白减少和 EphA4 水平增加相一致。我们的研究结果为一些患者抑郁症状的病因提供了深入的见解，并表明抑制 EphA4 或促进髓鞘形成可能是治疗抑郁症的一种有前途的策略。
