Mechanisms underlying cerebellar motor deficits due to mGluR1-autoantibodies.
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.
Coesmans
Michiel
M
Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands.
Smitt
Peter A Sillevis
PA
Linden
David J
DJ
Shigemoto
Ryuichi
R
Hirano
Tomoo
T
Yamakawa
Yoshinori
Y
van Alphen
Adriaan M
AM
Luo
Chongde
C
van der Geest
Josef N
JN
Kros
Johan M
JM
Gaillard
Carlo A
CA
Frens
Maarten A
MA
de Zeeuw
Chris I
CI
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
D001323:Autoantibodies; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1