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

Background: Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gammaaminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABAA 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 alpha 6 and delta subunits, would fail to do so in mice lacking either subunit. Methods: 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 d wild-type and knockout (Gabrd(+/+), Gabrd(-/-)) and littermate alpha 6 wild-type and knockout (Gabra6(+/+), Gabra6(-/-)) mice were tested. Results: Gabrd(+/+) mice displayed tremor reduction at 3 mg/N 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. Discussion: The loss of anti-tremor efficacy with deletion of either d or alpha 6 GABAA 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.