Genetic essential tremor in γ-aminobutyric acid A 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

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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-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 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.

Original languageEnglish (US)
Pages (from-to)774-779
Number of pages6
JournalJournal of Clinical Investigation
Volume115
Issue number3
DOIs
StatePublished - Mar 1 2005

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Aminobutyrates
Essential Tremor
Tremor
Knockout Mice
GABA-A Receptors
Primidone
Pregnanolone
Nitrendipine
Dizocilpine Maleate
Purkinje Cells
Diazepam
Propranolol
Ethanol
Adenosine A1 Receptor Agonists
Efferent Pathways
Drug Therapy
Genetic Models
Movement Disorders
Ataxia
N-Methyl-D-Aspartate Receptors

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Kralic, J. E., Criswell, H. E., Osterman, J. L., O'Buckley, T. K., Wilkie, M. E., Matthews, D. B., ... Morrow, A. L. (2005). Genetic essential tremor in γ-aminobutyric acid A receptor α1 subunit knockout mice Journal of Clinical Investigation, 115(3), 774-779. https://doi.org/10.1172/JCI200523625

Genetic essential tremor in γ-aminobutyric acid A receptor α1 subunit knockout mice . / 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.

In: Journal of Clinical Investigation, Vol. 115, No. 3, 01.03.2005, p. 774-779.

Research output: Contribution to journalArticle

Kralic, JE, Criswell, HE, Osterman, JL, O'Buckley, TK, Wilkie, ME, Matthews, DB, Hamre, K, Breese, GR, Homanics, GE & Morrow, AL 2005, ' Genetic essential tremor in γ-aminobutyric acid A receptor α1 subunit knockout mice ', Journal of Clinical Investigation, vol. 115, no. 3, pp. 774-779. https://doi.org/10.1172/JCI200523625
Kralic JE, Criswell HE, Osterman JL, O'Buckley TK, Wilkie ME, Matthews DB et al. Genetic essential tremor in γ-aminobutyric acid A receptor α1 subunit knockout mice Journal of Clinical Investigation. 2005 Mar 1;115(3):774-779. https://doi.org/10.1172/JCI200523625
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. / Genetic essential tremor in γ-aminobutyric acid A receptor α1 subunit knockout mice In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 3. pp. 774-779.
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