Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice

J Clin Invest. 2005 Mar;115(3):774-9. doi: 10.1172/JCI23625.

Abstract

Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that gamma-aminobutyric acidA (GABA(A)) receptor alpha1-/- mice exhibit postural and kinetic tremor and motor incoordination that is characteristic of essential tremor disease. We tested mice with essential-like tremor using current drug therapies that alleviate symptoms in essential tremor patients (primidone, propranolol, and gabapentin) and several candidates hypothesized to reduce tremor, including ethanol; the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801; the adenosine A1 receptor agonist 2-chloro-N6-cyclopentyladenosine (CCPA); the GABA(A) receptor modulators diazepam, allopregnanolone, and Ro15-4513; and the L-type Ca2+ channel antagonist nitrendipine. Primidone, propranolol, and gabapentin reduced the amplitude (power) of the pathologic tremor. Nonsedative doses of ethanol eliminated tremor in mice. Diazepam, allopregnanolone, Ro15-4513, and nitrendipine had no effect or enhanced tremor, whereas MK-801 and CCPA reduced tremor. To understand the etiology of tremor in these mice, we studied the electrophysiological properties of cerebellar Purkinje cells. Cerebellar Purkinje cells in GABA(A) receptor alpha1-/- mice exhibited a profound loss of all responses to synaptic or exogenous GABA, but no differences in abundance, gross morphology, or spontaneous synaptic activity were observed. This genetic animal model elucidates a mechanism of GABAergic dysfunction in the major motor pathway and potential targets for pharmacotherapy of essential tremor.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Anticonvulsants / pharmacology
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Essential Tremor / drug therapy
  • Essential Tremor / genetics*
  • Essential Tremor / metabolism*
  • Ethanol / therapeutic use
  • Excitatory Amino Acid Antagonists / pharmacology
  • Humans
  • Mice
  • Mice, Knockout
  • Motor Activity / physiology
  • Patch-Clamp Techniques
  • Primidone / pharmacology
  • Propranolol / pharmacology
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*

Substances

  • Adrenergic beta-Antagonists
  • Anticonvulsants
  • Excitatory Amino Acid Antagonists
  • Protein Subunits
  • Receptors, GABA-A
  • Primidone
  • Ethanol
  • Dizocilpine Maleate
  • Propranolol