Mandolesi Georgia, Gentile Antonietta, Musella Alessandra, Centonze Diego
Fondazione Santa Lucia IRCSS, Via del Fosso di Fiorano 64, 00146, Rome, Italy,
Cerebellum. 2015 Feb;14(1):19-22. doi: 10.1007/s12311-014-0613-0.
Multiple sclerosis (MS) is considered as an autoimmune inflammatory disease and is one of the main causes of motor disability in young adults. Focal white matter lesions consisting of T lymphocyte and macrophage infiltrates, demyelination, and axonal transection are clear hallmarks of MS disease. However, white matter pathology does not occur exclusively. Clinical and experimental studies have shown gray matter atrophy and lesions occurring in several brain regions, including the cerebellum. Cerebellar-dependent disability is very common in MS patients. Cerebellar deficits are also relatively refractory to symptomatic therapy and progress even under disease-modifying agents. However, the neuropathology underlying cerebellar dysfunction remains largely unknown. We recently demonstrated that the cerebellum is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. Electrophysiological studies, supported by immunofluorescence and biochemical analysis, revealed an imbalance between the spontaneous excitatory and inhibitory synaptic transmission at Purkinje cell synapses. While the frequency of the spontaneous inhibitory postsynaptic currents (sIPSC) during the acute phase of EAE was reduced in correlation with a selective degeneration of basket and stellate neurons, the glutamatergic transmission was enhanced due to a reduced expression and functioning of glutamate aspartate transporter (GLAST)/excitatory amino acid transporter 1 (EAAT1), the most abundant glutamate transporter expressed by Bergmann glia. Of note, we demonstrated that the proinflammatory cytokine interleukin-1β (IL-1β), highly expressed in EAE cerebellum and released by infiltrating lymphocytes, was one of the molecular players directly responsible for such synaptic alterations during the acute phase. Furthermore, other brain regions in EAE mice seem to be affected by a similar inflammatory dependent synaptopathy, suggesting common molecular targets for potential therapeutic strategies. Accordingly, we observed that intracerebroventricular inhibition of IL-1β signaling in EAE mice was able to ameliorate inflammatory reaction, electrophysiological response, and clinical disability, indicating a pivotal role of IL-1β in EAE disease and likely, in MS.
多发性硬化症（MS）被认为是一种自身免疫性炎症性疾病，是年轻成年人运动功能障碍的主要原因之一。由T淋巴细胞和巨噬细胞浸润、脱髓鞘和轴突横断组成的局灶性白质病变是MS疾病的明显特征。然而，白质病理并非唯一发生的情况。临床和实验研究表明，包括小脑在内的几个脑区会出现灰质萎缩和病变。小脑依赖性残疾在MS患者中非常常见。小脑功能缺陷对症状性治疗也相对难治，即使在使用疾病修饰药物的情况下仍会进展。然而，小脑功能障碍背后的神经病理学在很大程度上仍然未知。我们最近证明，在实验性自身免疫性脑脊髓炎（EAE）中，小脑也是靶点，EAE是MS最广泛使用的动物模型。在免疫荧光和生化分析的支持下，电生理研究揭示了浦肯野细胞突触处自发兴奋性和抑制性突触传递之间的失衡。在EAE急性期，自发抑制性突触后电流（sIPSC）的频率降低，这与篮状神经元和星状神经元的选择性退化相关，而由于谷氨酸天冬氨酸转运体（GLAST）/兴奋性氨基酸转运体1（EAAT1）的表达和功能降低，谷氨酸能传递增强，EAAT1是伯格曼胶质细胞表达最丰富的谷氨酸转运体。值得注意的是，我们证明促炎细胞因子白细胞介素-1β（IL-1β）在EAE小脑中高度表达并由浸润淋巴细胞释放，是急性期这种突触改变的直接分子参与者之一。此外，EAE小鼠的其他脑区似乎也受到类似的炎症依赖性突触病变的影响，这表明潜在治疗策略有共同的分子靶点。因此，我们观察到，在EAE小鼠中脑室内抑制IL-1β信号能够改善炎症反应、电生理反应和临床残疾，表明IL-1β在EAE疾病以及可能在MS中起关键作用。
