Genetic essential tremor in γ-aminobutyric acidA receptor α1 subunit knockout mice
Jason E. Kralic, … , Gregg E. Homanics, A. Leslie Morrow
Jason E. Kralic, … , Gregg E. Homanics, A. Leslie Morrow
Published March 1, 2005
Citation Information: J Clin Invest. 2005;115(3):774-779. https://doi.org/10.1172/JCI23625.
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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 normal Purkinje cell number and morpho...
GABAA receptor α1–/– mice exhibit normal Purkinje cell number and morphology but complete loss of both spontaneous mIPSCs and exogenous GABA inhibition of whole-cell voltage-clamp electrophysiological responses. (A) Calbindin staining of Purkinje cell number and morphology in cerebellum of 8-month-old α1+/+ and α1–/– mice. Magnification, ×400. (B) Similar spontaneously active Purkinje cells were found in both α1+/+ (22 of 29 penetrations) and α1–/– (28 of 36 penetrations) mice. Mean rate for α1–/– mice (26.7 ± 3.8) did not differ from that of α1+/+ mice (32.4 ± 5.5). (C) Spontaneous mIPSCs recorded over a 30-second period from a Purkinje cell mechanically dissociated from an α1+/+ and α1–/– mouse. Spontaneous postsynaptic picrotoxin-sensitive currents with amplitude greater than 50 pA and fall-times greater than 4 ms were recorded from 10 of 16 α1+/+ mice and 0 of 14 α1–/– mice. (D) Whole-cell voltage-clamp recordings were obtained from mechanically dissociated cerebellar Purkinje cells from α1+/+ and α1–/– mice. GABA was applied to the neurons by a U-tube. GABA (3, 30, and 100 μM) gated a concentration-dependent inward current when applied to Purkinje cells from α1+/+ mice, but no current was gated in α1–/– Purkinje cells. (E) Mean GABA-gated currents from cerebellar Purkinje cells mechanically isolated from α1+/+ or α1–/– mice. There was a statistically reliable concentration-related increase in GABA response in the α1+/+ mice (*P < 0.001) but no effect of GABA in the α1–/– mice (P > 0.1) (n = 6–11 neurons per group).