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

• Published in: The Journal of clinical investigation 2005-03, Vol.115 (3), p.774-779
• Main Authors: Kralic, Jason E., Criswell, Hugh E., Osterman, Jessica L., O’Buckley, Todd K., Wilkie, Mary E., Matthews, Douglas B., Hamre, Kristin, Breese, George R., Homanics, Gregg E., Morrow, A. Leslie
• Format: Article
• Language: English
• ISSN: 0021-9738
• DOI: 10.1172/JCI200523625

Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that γ-aminobutyric acid A (GABA A ) receptor α 1 –/– 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 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 α 1 –/– 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.