title: Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum.
abstract: Structural changes in Purkinje cells have been identified in the essential tremor cerebellum, although the mechanisms that underlie these changes remain poorly understood. Climbing fibres provide one of the major excitatory inputs to Purkinje cells, and climbing fibre-Purkinje cell connections are essential for normal cerebellar-mediated motor control. The distribution of climbing fibre-Purkinje cell synapses on Purkinje cell dendrites is dynamically regulated and may be altered in disease states. The aim of the present study was to examine the density and distribution of climbing fibre-Purkinje cell synapses using post-mortem cerebellar tissue of essential tremor cases and controls. Using vesicular glutamate transporter type 2 immunohistochemistry, we labelled climbing fibre-Purkinje cell synapses of 12 essential tremor cases and 13 age-matched controls from the New York Brain Bank. Normally, climbing fibres form synapses mainly on the thick, proximal Purkinje cell dendrites in the inner portion of the molecular layer, whereas parallel fibres form synapses on the thin, distal Purkinje cell spiny branchlets. We observed that, compared with controls, essential tremor cases had decreased climbing fibre-Purkinje cell synaptic density, more climbing fibres extending to the outer portion of the molecular layer, and more climbing fibre-Purkinje cell synapses on the thin Purkinje cell spiny branchlets. Interestingly, in essential tremor, the increased distribution of climbing fibre-Purkinje cell synapses on the thin Purkinje cell branchlets was inversely associated with clinical tremor severity, indicating a close relationship between the altered distribution of climbing fibre-Purkinje cell connections and tremor. These findings suggest that abnormal climbing fibre-Purkinje cell connections could be of importance in the pathogenesis of essential tremor.
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors.forename: Chi-Ying
authors.initials: CY
authors.lastname: Lin
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA 2 GH Sergievsky Centre, Columbia University, New York, NY, USA 3 Taub Institute for Research of Alzheimer's disease and the Aging Brain, Columbia University, New York, NY, USA 4 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
authors.forename: Elan D
authors.initials: ED
authors.lastname: Louis
authors.affiliation: 5 Department of Pathology and Cell Biology, Columbia University Medical Centre and the New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Phyllis L
authors.initials: PL
authors.lastname: Faust
authors.affiliation: 6 Neurology and Research Services, Veterans Affairs Medical Centre, Albany, NY, USA 7 Departments of Neurology and Pathology, Albany Medical College, Albany, NY, USA.
authors.forename: Arnulf H
authors.initials: AH
authors.lastname: Koeppen
authors.affiliation: 3 Taub Institute for Research of Alzheimer's disease and the Aging Brain, Columbia University, New York, NY, USA 5 Department of Pathology and Cell Biology, Columbia University Medical Centre and the New York Presbyterian Hospital, New York, NY, USA.
authors.forename: Jean-Paul G
authors.initials: JP
authors.lastname: Vonsattel
authors.affiliation: 1 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA sk3295@cumc.columbia.edu.
authors.forename: Sheng-Han
authors.initials: SH
authors.lastname: Kuo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D002531:Cerebellum / Q000473:pathology*; D003712:Dendrites / Q000473:pathology*; D020329:Essential Tremor / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D009412:Nerve Fibers / Q000473:pathology; D011689:Purkinje Cells / Q000473:pathology*; D013569:Synapses / Q000473:pathology*
keywords: Purkinje cell; VGlut2; climbing fibre; essential tremor; synapse