期刊
BRAIN
卷 137, 期 -, 页码 3149-3159出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awu281
关键词
essential tremor; climbing fibre; Purkinje cell; synapse; VGlut2
资金
- NINDS [K08 NS083738, R21 NS077094, R01 NS39422]
- Louis V. Gerstner Jr Scholar Award
- Parkinson's Disease Foundation
- American Brain Foundation Research Fellowship
- American Parkinson's Disease Association
- International Essential Tremor Foundation
- National Institutes of Health: NINDS [R21 NS077094, R01 NS39422, R01 NS042859, R01 NS086736, R01 NS073872, R01 NS085136, T32 NS07153-24, R01 NS36630]
- National Institutes of Health: NIEHS [P30 ES09089]
- National Institutes of Health: CTSA [UL1 RR024156]
- Arlene Bronstein Essential Tremor Research Fund (Columbia University)
- Claire O'Neil Essential Tremor Research Fund (Columbia University)
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 postmortem 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.
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