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 acid A (GABA A ) 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-Daspartate 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 Ca 2+ 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 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.

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

“…Patch clamp recording analyses showed a complete loss of spontaneous and evoked IPSCs and no compensation by strychninesensitive glycine receptors (9,86). No evidence for tonic inhibition could be found either in PC of a1 0/0 mice.…”

Genetic mouse models of essential tremor: are they essential?

“…Moreover, the reported appearance in mice of a pathologic tremor at a frequency of 19 Hz is substantially higher than the 4-to 8-Hz tremor frequency typically observed in human ET. Since a continuous or gait-induced axial tremor of 10-14 Hz measured on the cage floor is typically seen in various drug-induced and single-gene mouse models of ET, the higher frequency (19 Hz) of the pathologic tremor described by Kralic et al (14) is not simply due to the small size of the mouse, as the authors suggest. Instead, it is likely to be either an artifact of the in-air tail suspension recording technique or a specific characteristic of mice with the GABA A receptor α1 subunit deletion.…”

“…In this issue of the JCI, Kralic et al (14) describe a novel genetic model of ET in γ-aminobutyric acid A (GABA A ) receptor α1 subunit knockout (GABA A receptor α1 -/-) mice. GABA A receptors are a heterogeneous family of ligand-gated chloride channels, each composed of 5 protein subunits (2 α, 2 β, and 1 γ) encoded by 18 different genes.…”

“…These channel subunits are differentially expressed in different regions, conferring a spectrum of pharmacological properties to synaptic inhibitory signaling throughout the central nervous system. Mice deficient in the α1 subunit display an action tremor, and Kralic et al (14) propose that the mutant is a promising model of ET because the tremor is prominent in the limbs, is pronounced upon tail suspension yet absent when the mouse is relaxed, and improves with administration of primidone, propranolol, and ethanol -the 3 agents most consistently effective in the treatment of ET.…”

“…Since these alternative receptors vary in kinetic behavior and pharmacology according to cell type and region, characterizing inhibitory transmission in the mutant nervous system will be a lengthy process, and the design of an effective drug to target this altered pattern may be dependent upon both age and region (21). The authors postulate that the tremor in GABA A receptor α1 -/-mice may result from a loss of GABA A signaling by cerebellar purkinje cells but without actual degeneration of the cells (14). This would be consistent with the pathological studies in ET, which have so far not demonstrated microscopic cerebellar pathology in postmortem brains of patients with ET (22).…”