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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

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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 3

Syt2 deletion from the cerebellum is sufficient to generate an action tremor.

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Syt2 deletion from the cerebellum is sufficient to generate an action tr...
(A) Stereotactic injection strategy of AAVs encoding Cre-GFP into 1 of 4 brain regions: the motor cortex (MO), basal ganglia (BG), thalamus (TH), or cerebellum (CB). (B) Top, a representative image showing the expression of Cre-GFP in the cerebellum of Syt2fl/fl mice; bottom, power spectrum of force-plate measurements from the same mouse before and after viral injection. Also see Supplemental Video 5 and Supplemental Figure 5. (C) Summary graph of the tremor index before and after injections of AAV Cre-GFP into different brain regions (n = 5 MO, n = 6 BG, n = 5 TH, n = 7 CB). Please see the methods section for our approaches to infect these large brain areas. For C, data are shown as means ± SEM from at least 3 independent litters. ***P < 0.001 by 2-sided, paired t test. Scale bar: 1 mm (B).

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