Genetic essential tremor in γ-aminobutyric acidA receptor α1 subunit knockout mice
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
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
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Article Neuroscience

Genetic essential tremor in γ-aminobutyric acidA receptor α1 subunit knockout mice

Abstract

Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acidA (GABAA) receptor α1–/– 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 GABAA 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 GABAA receptor α1–/– 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

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GABAA receptor α1–/– mice exhibit essential-like tremor. Normal physiolo...
GABAA receptor α1–/– mice exhibit essential-like tremor. Normal physiologic tremor (wide range of low-power frequencies, 25–40 Hz) was observed in α1+/+, α1+/–, and α1–/– mice. Knockout mice also exhibited pathologic tremor (small range of high-power frequencies, 17–21 Hz) characteristic of essential tremor. Representative voltage tracings and Fourier transformation of tremor-induced displacement is shown for α1+/+ (A), α1+/– (B), and α1–/– (C) mice. (A) α1+/+ mice exhibit a tremor with a mean maximal power of 2.6 × 1011 ± 3.2 × 1011 N and a mean frequency of 32.1 ± 0.6 Hz (n = 16); (B) α1+/– mice, mean maximal power of 6.0 × 1011 ± 1.1 × 1011 N and mean frequency of 35.0 ± 1.9 Hz (n = 5); (C) α1–/– mice, mean maximal power of 24.3 × 1011 ± 4.2 × 1011 N and mean frequency of 19.3 ± 0.9 Hz (n = 13). Tremor is plotted as the voltage generated upon displacement of the transducer as a function of time (seconds). The power of individual frequencies that contribute to the overall tremor was determined by Fourier transformation of the voltage trace over time.