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

• Main Authors: Adrian Handforth, Pournima A. Kadam, Hovsep P. Kosoyan, Pirooz Eslami
• Format: Article
• Language: English
• Published: Ubiquity Press 2018-06-01
• Series: Tremor and Other Hyperkinetic Movements
• Subjects: Harmaline; GABA; Cerebellum; Tremor; Harmaline tremor; Essential tremor; Neurology; Gamma-aminobutyric acid
• Online Access: https://tremorjournal.org/index.php/tremor/browse?&year=2018results=10&page=3
• ISSN: 2160-8288; 2160-8288

Background: 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 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 α6 and δsubunits, 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 δ wild-type and knockout (Gabrd+/+, Gabrd–/–) and littermate α6 wild-type and knockout (Gabra6+/+, Gabra6–/–) mice were tested. Results: 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. Discussion: The loss of anti-tremor efficacy with deletion of either δ or α6 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.