Coesmans Michiel, Smitt Peter A Sillevis, Linden David J, Shigemoto Ryuichi, Hirano Tomoo, Yamakawa Yoshinori, van Alphen Adriaan M, Luo Chongde, van der Geest Josef N, Kros Johan M, Gaillard Carlo A, Frens Maarten A, de Zeeuw Chris I
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
Ann Neurol. 2003 Mar;53(3):325-36. doi: 10.1002/ana.10451.
Patients with Hodgkin's disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1 (mGluR1-Abs). Yet, the pathophysiological mechanisms underlying their motor coordination deficits remain to be elucidated. Here, we show that application of IgG purified from the patients' serum to cerebellar slices of mice acutely reduces the basal activity of Purkinje cells, whereas application to the flocculus of mice in vivo evokes acute disturbances in the performance of their compensatory eye movements. In addition, the mGluR1-Abs block induction of long-term depression in cultured mouse Purkinje cells, whereas the cerebellar motor learning behavior of the patients is affected in that they show impaired adaptation of their saccadic eye movements. Finally, postmortem analysis of the cerebellum of a paraneoplastic cerebellar ataxia patient showed that the number of Purkinje cells was significantly reduced by approximately two thirds compared with three controls. We conclude that autoantibodies against mGluR1 can cause cerebellar motor coordination deficits caused by a combination of rapid effects on both acute and plastic responses of Purkinje cells and chronic degenerative effects.
霍奇金淋巴瘤患者可因产生针对代谢型谷氨酸受体1的自身抗体（mGluR1-Abs）而发生副肿瘤性小脑共济失调。然而，其运动协调障碍背后的病理生理机制仍有待阐明。在此，我们表明，将从患者血清中纯化的IgG应用于小鼠小脑切片可急性降低浦肯野细胞的基础活性，而在小鼠体内应用于绒球则会引发其代偿性眼球运动表现的急性紊乱。此外，mGluR1-Abs可阻断培养的小鼠浦肯野细胞中长时程抑制的诱导，而患者的小脑运动学习行为受到影响，表现为扫视眼运动的适应性受损。最后，对一名副肿瘤性小脑共济失调患者的小脑进行尸检分析发现，与三名对照相比，浦肯野细胞数量显著减少了约三分之二。我们得出结论，针对mGluR1的自身抗体可通过对浦肯野细胞的急性和可塑性反应的快速作用以及慢性退行性作用的综合作用导致小脑运动协调障碍。
