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

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.

• Authors: Jason E Kralic, Hugh E Criswell, Jessica L Osterman, Todd K O'Buckley, Mary E Wilkie, Douglas B Matthews, Kristin Hamre, George R Breese, Gregg E Homanics, A Leslie Morrow
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 115 Issue 3 Pg. 774-9 (Mar 2005) ISSN: 0021-9738 [Print] United States
• PMID: 15765150 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

• Adrenergic beta-Antagonists (pharmacology)
• Animals
• Anticonvulsants (pharmacology)
• Disease Models, Animal
• Dizocilpine Maleate (pharmacology)
• Essential Tremor (drug therapy, genetics, 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, metabolism)
• Receptors, GABA-A (genetics, metabolism)