title: Defective dentate nucleus GABA receptors in essential tremor.
abstract: 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 (↓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.
authors: Faculty of Pharmacy, Laval University, Quebec, QC G1V 0A6, Canada.
authors: Sarah
authors: S
authors: Paris-Robidas
authors: Elodie
authors: E
authors: Brochu
authors: Marion
authors: M
authors: Sintes
authors: Vincent
authors: V
authors: Emond
authors: Mélanie
authors: M
authors: Bousquet
authors: Milène
authors: M
authors: Vandal
authors: Mireille
authors: M
authors: Pilote
authors: Cyntia
authors: C
authors: Tremblay
authors: Thérèse
authors: T
authors: Di Paolo
authors: Ali H
authors: AH
authors: Rajput
authors: Alex
authors: A
authors: Rajput
authors: Frédéric
authors: F
authors: Calon
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001345:Autoradiography; D002529:Cerebellar Nuclei / Q000378:metabolism*; D020329:Essential Tremor / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000235:genetics / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D018080:Receptors, GABA-B