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: Sarah Paris-Robidas, Elodie Brochu, Marion Sintes, Vincent Emond, Mélanie Bousquet, Milène Vandal, Mireille Pilote, Cyntia Tremblay, Thérèse Di Paolo, Ali H Rajput, Alex Rajput, Frédéric Calon
• Journal: Brain : a journal of neurology (Brain) Vol. 135 Issue Pt 1 Pg. 105-16 (Jan 2012) ISSN: 1460-2156 [Electronic] England
• PMID: 22120148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, GABA-A
• Receptors, GABA-B

Topics

• Aged
• Aged, 80 and over
• Autoradiography
• Cerebellar Nuclei (metabolism)
• Essential Tremor (genetics, metabolism)
• Female
• Humans
• Male
• Parkinson Disease (genetics, metabolism)
• Receptors, GABA-A (genetics, metabolism)
• Receptors, GABA-B (genetics, metabolism)