Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies

Michiel Coesmans, Peter A. Sillevis Smitt, David J. Linden, Ryuichi Shigemoto, Tomoo Hirano, Yoshinori Yamakawa, Adriaan M. Van Alphen, Chongde Luo, Josef N. Van der Geest, Johan M. Kros, Carlo A. Gaillard, Maarten A. Frens, Chris I. De Zeeuw

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)325-336
Number of pages12
JournalAnnals of neurology
Volume53
Issue number3
DOIs
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Coesmans, M., Sillevis Smitt, P. A., Linden, D. J., Shigemoto, R., Hirano, T., Yamakawa, Y., Van Alphen, A. M., Luo, C., Van der Geest, J. N., Kros, J. M., Gaillard, C. A., Frens, M. A., & De Zeeuw, C. I. (2003). Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies. Annals of neurology, 53(3), 325-336. https://doi.org/10.1002/ana.10451