Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice.
Essential tremor is the most common movement disorder and has an unknown etiology. Here we report that gamma-aminobutyric acidA (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, 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 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.
Kralic
Jason E
JE
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599-7178, USA.
Criswell
Hugh E
HE
Osterman
Jessica L
JL
O'Buckley
Todd K
TK
Wilkie
Mary E
ME
Matthews
Douglas B
DB
Hamre
Kristin
K
Breese
George R
GR
Homanics
Gregg E
GE
Morrow
A Leslie
AL
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D020329:Essential Tremor / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000431:Ethanol / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D018408:Patch-Clamp Techniques; D011324:Primidone / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011324:Primidone; D000431:Ethanol; D016291:Dizocilpine Maleate; D011433:Propranolol