Dysfunction of parvalbumin neurons in the cerebellar nuclei produces an action tremor
Mu Zhou, … , Wei Xu, Thomas C. Südhof
Mu Zhou, … , Wei Xu, Thomas C. Südhof
Published July 7, 2020
Citation Information: J Clin Invest. 2020;130(10):5142-5156. https://doi.org/10.1172/JCI135802.
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Research Article Neuroscience

Dysfunction of parvalbumin neurons in the cerebellar nuclei produces an action tremor

Abstract

Essential tremor is a common brain disorder affecting millions of people, yet the neuronal mechanisms underlying this prevalent disease remain elusive. Here, we showed that conditional deletion of synaptotagmin-2, the fastest Ca2+ sensor for synaptic neurotransmitter release, from parvalbumin neurons in mice caused an action tremor syndrome resembling the core symptom of essential tremor patients. Combining brain region–specific and cell type–specific genetic manipulation methods, we found that deletion of synaptotagmin-2 from excitatory parvalbumin-positive neurons in cerebellar nuclei was sufficient to generate an action tremor. The synaptotagmin-2 deletion converted synchronous into asynchronous neurotransmitter release in projections from cerebellar nuclei neurons onto gigantocellular reticular nucleus neurons, which might produce an action tremor by causing signal oscillations during movement. The tremor was rescued by completely blocking synaptic transmission with tetanus toxin in cerebellar nuclei, which also reversed the tremor phenotype in the traditional harmaline-induced essential tremor model. Using a promising animal model for action tremor, our results thus characterized a synaptic circuit mechanism that may underlie the prevalent essential tremor disorder.

Authors

Mu Zhou, Maxwell D. Melin, Wei Xu, Thomas C. Südhof

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Figure 9

Model for the generation of action tremor.

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Model for the generation of action tremor. (A) Schematic diagram of the ...
(A) Schematic diagram of the neural circuit controlling the real-time correction of movement command signals. (B) Simplified simulation showing how delayed online movement correction could generate oscillatory movement. Here the planned path is a straight line from (0, 0) to (13, 0); assuming movement at (2, 0) is deviated to (2, 1) due to a perturbation. In healthy animals, the movement is compensated by the y axis “correction” signal “–1” in real time and continues its planned trajectory. In action tremor animals, we posit the correction signal is delayed by a fixed time period (time needed to move between 2 ticks on the x axis), as shown by the row of numbers in red at the bottom. The deviated movement at (2, 1) is not compensated and continues on the wrong trajectory to (3, 2), where it starts to be partially compensated by the delayed correction signal –1. Continuing with this delayed y axis correction, the movement exhibits an oscillatory pattern. In this simplified simulation, as the duration of the fixed temporal delay increases, tremor amplitude increases and frequency decreases.