Research ArticleESSENTIAL TREMOR

Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology

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Science Translational Medicine  15 Jan 2020:
Vol. 12, Issue 526, eaay1769
DOI: 10.1126/scitranslmed.aay1769

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Shake the tremor off

Essential tremor (ET) is a neurological disorder characterized by involuntary rhythmic movements of part of the body. The mechanisms underlying ET development are not completely elucidated. Using autoptic brain tissue, mouse models, and EEG analysis in patients, Pan et al. demonstrated that subjects with ET had excessive cerebellar oscillations that correlated with tremor severity. Mechanistic work showed that the excessive oscillations triggered glutamate receptor delta 2 (GluRδ2) insufficiency and synaptic pruning impairment at climbing fiber–to–Purkinje cell synapses in the cerebellum. Rescuing GluRδ2 reduced cerebellar oscillations and rescued tremor in mice.

Abstract

Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)–to–Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

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