Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 3, Pages 774-779Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200523625
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Funding
- NIAAA NIH HHS [AA11605, R01 AA010422, AA10422, R37 AA010422, AA09013, P50 AA011605, P60 AA011605] Funding Source: Medline
- NIGMS NIH HHS [GM52035] Funding Source: Medline
- NIMH NIH HHS [MH61971, U01 MH061971] Funding Source: Medline
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Essential tremor is the most common movement disorder and has in unknown etiology. Here we report that gamma-aminobutyric acid(A) (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, allopregnanollone, 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.
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