Research ArticleNeurodegenerative Disease

Decreased Tonic Inhibition in Cerebellar Granule Cells Causes Motor Dysfunction in a Mouse Model of Angelman Syndrome

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Science Translational Medicine  05 Dec 2012:
Vol. 4, Issue 163, pp. 163ra157
DOI: 10.1126/scitranslmed.3004655

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Elucidating the Mechanism of Ataxia in Angelman Syndrome

Angelman syndrome is a neurodevelopmental disorder caused by loss of the ubiquitin E3 ligase Ube3a. A variety of symptoms, including severe developmental delay, speech impairment, epilepsy, and movement and balance problems, are associated with Angelman syndrome. In a new study, Egawa et al. investigate electrophysiological features of cerebellar dysfunction in a mouse model of Angelman syndrome. The authors report that extrasynaptic γ-aminobutyric acid type A (GABAA) receptor–mediated tonic inhibition decreases in cerebellar granule cells from the Ube3a-deficient Angelman mice. They then show that, normally, Ube3a binds to GABA transporter 1, a key modulator of extrasynaptic GABA, and controls its degradation in the mouse cerebellum. The Ube3a-deficient mice, however, showed a surplus of GABA transporter 1, resulting in decreased GABA concentrations in the extrasynaptic space and thus decreased tonic inhibition of cerebellar granule cells. Pharmacological compensation of decreased tonic inhibition by administering low doses of THIP, a selective agonist of extrasynaptic GABAA receptors, alleviated impaired motor function in the Ube3a-deficient mice. Thus, attenuated GABA transporter 1 degradation and a consequent decrease in tonic inhibition of cerebellar granule cells play a key role in the cerebellar dysfunction characteristic of Angelman syndrome. Pharmacologically increasing tonic inhibition with THIP may be a useful strategy for alleviating movement and balance problems in patients with this disease.

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