title: Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.
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.
authors.affiliation: Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Michiel
authors.initials: M
authors.lastname: Coesmans
authors.forename: Peter A Sillevis
authors.initials: PA
authors.lastname: Smitt
authors.forename: David J
authors.initials: DJ
authors.lastname: Linden
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Shigemoto
authors.forename: Tomoo
authors.initials: T
authors.lastname: Hirano
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamakawa
authors.forename: Adriaan M
authors.initials: AM
authors.lastname: van Alphen
authors.forename: Chongde
authors.initials: C
authors.lastname: Luo
authors.forename: Josef N
authors.initials: JN
authors.lastname: van der Geest
authors.forename: Johan M
authors.initials: JM
authors.lastname: Kros
authors.forename: Carlo A
authors.initials: CA
authors.lastname: Gaillard
authors.forename: Maarten A
authors.initials: MA
authors.lastname: Frens
authors.forename: Chris I
authors.initials: CI
authors.lastname: de Zeeuw
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000009:adverse effects* / Q000097:blood / Q000494:pharmacology; D002478:Cells, Cultured; D002526:Cerebellar Diseases / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D006689:Hodgkin Disease / Q000097:blood / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009048:Motor Skills / Q000187:drug effects / Q000502:physiology; D020362:Paraneoplastic Cerebellar Degeneration / Q000473:pathology / Q000503:physiopathology; D011689:Purkinje Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000097:blood / Q000276:immunology*; D012438:Saccades / Q000502:physiology
chemical_list: D001323:Autoantibodies; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1