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

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.

Purkinje cell neurotransmission patterns cerebellar basket cells into zonal modules defined by distinct pinceau sizes

“…Both of these motor diseases appear late in life and have been associated with significant Purkinje cells loss. The abnormal electrophysiological properties of Purkinje cells prior to their loss in these disorders is currently a subject of intense study ( Watase et al, 2008 ; Jayabal et al, 2016 ; Kralic et al, 2005 ; Brown et al, 2020 ; Pan et al, 2020 ). Whether the loss of Purkinje cell neurotransmission coupled with the loss of the cells themselves or a disruption in their normal communication properties prior to cell death affects the organization of pinceaux zones per se has not yet been tested.…”

Deep-Brain Stimulation for Essential Tremor and Other Tremor Syndromes: A Narrative Review of Current Targets and Clinical Outcomes

“…This reduces the GABAergic input to cerebellar output nuclei, inducing excessive cerebellar output to the thalamus. Combined with a chronic reorganization or the remaining Purkinje cell synapses in the cerebellar cortex, oscillations arise in motor networks that generate an action tremor [83]. Most patients with ET initially respond to propranolol or GABAergic agents, such as topiramate, gabapentin, primidone and ethanol [84].…”

Excessive Cerebellar Oscillations in Essential Tremor: Insights Into Disease Mechanism and Treatment

“…In an attempt to elucidate a plausible pathomechanism in ET, Pan and colleagues showed how excessive cerebellar oscillations correlate with tremor severity . First, cerebellar tissues of 15 typical ET patients and age‐matched controls were examined.…”