Cognitive impairment is often observed in multiple sclerosis and its animal models, experimental autoimmune encephalomyelitis (EAE). Using mice with immunization-induced EAE, we have previously shown that the stability of cortical synapses is markedly decreased before the clinical onset of EAE. In this study, we examined learning-dependent structural synaptic plasticity in a spontaneous EAE model. Transgenic mice expressing myelin basic protein-specific T cell receptor genes develop EAE spontaneously at around 8 weeks of age. Using in vivo two-photon microscopy, we found that the elimination and formation rates of postsynaptic dendritic spines in somatosensory and motor cortices increased weeks before detectable signs of EAE and remained to be high during the disease onset. Despite the elevated basal spine turnover, motor learning-induced spine formation was reduced in presymptomatic EAE mice, in line with their impaired ability to retain learned motor skills. Additionally, we found a substantial elevation of IFN-γ mRNA in the brain of 4-week-old presymptomatic mice, and treatment of anti-IFN-γ antibody reduced dendritic spine elimination in the cortex. Together, these findings reveal synaptic instability and failure to form new synapses after learning as early brain pathology of EAE, which may contribute to cognitive and behavioral deficits seen in autoimmune diseases.

中文翻译：

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自发性自身免疫性脑脊髓炎的学习依赖性树突棘可塑性受损

在多发性硬化症及其动物模型、实验性自身免疫性脑脊髓炎 (EAE) 中经常观察到认知障碍。使用具有免疫诱导的 EAE 的小鼠，我们之前已经表明皮质突触的稳定性在 EAE 临床发作之前显着降低。在这项研究中，我们检查了自发 EAE 模型中的学习依赖性结构突触可塑性。表达髓鞘碱性蛋白特异性 T 细胞受体基因的转基因小鼠在 8 周龄左右自发发展 EAE。使用体内双光子显微镜，我们发现体感和运动皮层中突触后树突棘的消除和形成率在可检测到 EAE 迹象前几周增加，并且在疾病发作期间保持较高水平。尽管基底脊柱翻转率升高，症状前 EAE 小鼠的运动学习诱导的脊柱形成减少，这与它们保留学习的运动技能的能力受损一致。此外，我们发现 4 周大的症状前小鼠大脑中的 IFN-γ mRNA 显着升高，并且抗 IFN-γ 抗体的治疗减少了皮质中树突棘的消除。总之，这些发现揭示了作为 EAE 的早期脑病理学学习后突触不稳定和未能形成新突触，这可能导致自身免疫性疾病中出现的认知和行为缺陷。和抗 IFN-γ 抗体的治疗减少了皮质中树突棘的消除。总之，这些发现揭示了作为 EAE 的早期脑病理学学习后突触不稳定和未能形成新突触，这可能导致自身免疫性疾病中出现的认知和行为缺陷。和抗 IFN-γ 抗体的治疗减少了皮质中树突棘的消除。总之，这些发现揭示了作为 EAE 的早期脑病理学学习后突触不稳定和未能形成新突触，这可能导致自身免疫性疾病中出现的认知和行为缺陷。