Suppression of Harmaline Tremor by Activation of an Extrasynaptic GABA_A Receptor: Implications for Essential Tremor

Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gamma-aminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABA_A receptor-specific agonist THIP (gaboxadol; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) would suppress tremor in the harmaline model of essential tremor and, since cerebellar extrasynaptic receptors contain α6 and δ subunits, would fail to do so in mice lacking either subunit.

Digitally measured motion power, expressed as 10-16 Hz power (the tremor bandwidth) divided by background 8-32 Hz motion power, was accessed during pre-harmaline baseline, pre-THIP harmaline exposure, and after THIP administration (0, 2, or 3 mg/kg). These low doses were chosen as they did not impair performance on the straight wire test, a sensitive test for psychomotor impairment. Littermate δ wild-type and knockout (Gabrd^+/+, Gabrd^-/-) and littermate α6 wild-type and knockout (Gabra6^+/+, Gabra6 ) mice were tested.

Gabrd^+/+ mice displayed tremor reduction at 3 mg/kg THIP but not 2 mg/kg, and Gabra6^+/+ mice showed tremor reduction at 2 and 3 mg/kg. Their respective subunit knockout littermates displayed no tremor reduction compared with vehicle controls at either dose.

The loss of anti-tremor efficacy with deletion of either δ or α6 GABA_A receptor subunits indicates that extrasynaptic receptors containing both subunits, most likely located on cerebellar granule cells where they are highly expressed, mediate tremor suppression by THIP. A medication designed to activate only these receptors may display a favorable profile for treating essential tremor.