Journal
BRAIN
Volume 135, Issue -, Pages 105-116Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awr301
Keywords
essential tremor; cerebellum; GABA receptors; dentate nucleus; deep cerebellar nuclei
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Funding
- International Essential Tremor Foundation (IETF)
- Fonds d'Enseignement et de Recherche of the Faculty of Pharmacy of Laval University
- Canada Foundation for Innovation [10307]
- Canadian Institutes of Health Research [CAN-76833]
- Fonds de la recherche en sante du Quebec
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The development of new treatments for essential tremor, the most frequent movement disorder, is limited by a poor understanding of its pathophysiology and the relative paucity of clinicopathological studies. Here, we report a post-mortem decrease in GABA(A) (35% reduction) and GABA(B) (22-31% reduction) receptors in the dentate nucleus of the cerebellum from individuals with essential tremor, compared with controls or individuals with Parkinson's disease, as assessed by receptor-binding autoradiography. Concentrations of GABA(B) receptors in the dentate nucleus were inversely correlated with the duration of essential tremor symptoms (r(2) = 0.44, P < 0.05), suggesting that the loss of GABA(B) receptors follows the progression of the disease. In situ hybridization experiments also revealed a diminution of GABA(B(1a+b)) receptor messenger RNA in essential tremor (down arrow 27%). In contrast, no significant changes of GABA(A) and GABA(B) receptors (protein and messenger RNA), GluN2B receptors, cytochrome oxidase-1 or GABA concentrations were detected in molecular or granular layers of the cerebellar cortex. It is proposed that a decrease in GABA receptors in the dentate nucleus results in disinhibition of cerebellar pacemaker output activity, propagating along the cerebello-thalamo-cortical pathways to generate tremors. Correction of such defective cerebellar GABAergic drive could have a therapeutic effect in essential tremor.
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