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 GABAA (35 reduction) and GABAB (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 GABAB 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 GABAB receptors follows the progression of the disease. In situ hybridization experiments also revealed a diminution of GABAB(1a+b) receptor messenger RNA in essential tremor (↓27). In contrast, no significant changes of GABAA and GABAB 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. © 2011 The Author.