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.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 3

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

×

Figure 1

PVcre Syt2fl mice as an animal model for action tremor.

Options: View larger image (or click on image) Download as PowerPoint
PVcre Syt2fl mice as an animal model for action tremor. (A–C) Exemplary ...
(A–C) Exemplary tremor recordings on a force plate to illustrate the tremor observed in PVcre Syt2fl mice compared with PVcre Syt2wt mice. (A) Raw data of 3-second weight measurement using the force-plate actometer. (B) Spectrograph calculated from 20-minute force-plate measurements. (C) Averaged power spectrum from data in B. The tremor index was calculated by integrating the power in the 9-Hz to 12-Hz range and using the averaged power in the 3-Hz to 6-Hz range as baseline. (D) Correlation of the tremor index measured on a force plate and the tremor amplitude monitored simultaneously by video tracking in PVcre Syt2fl and control mice at different ages. (E) Power spectra of force-plate measurements from a representative PVcre Syt2fl mouse at different ages. (F) Summary plot of the tremor index of PVcre Syt2wt and PVcre Syt2fl mice as a function of age (n = 19 PVcre Syt2wt, n = 18 PVcre Syt2fl). (G) Summary plot of the tremor index of PVcre Syt2fl and control mice as a function of time after an s.c. injection of ethanol (EtOH); PVcre Syt2fl mice injected with saline used as a further control (n = 5 control + EtOH, n = 7 PVcre Syt2fl + saline, n = 6 PVcre Syt2fl + EtOH). (H) Exemplary simultaneous measurements of the movements and tremor in a PVcre Syt2fl mouse. Episodes longer than 3 seconds with speed less than 2.5 cm/s are indicated by vertical blue shaded bars. (I) Summary graph of the tremor index of PVcre Syt2fl mice before, during, and after periods of quiescence lasting longer than 3 seconds (n = 17). For F, G, and I, data are shown as means ± SEM from at least 3 independent litters. *P < 0.05; **P < 0.01; ***P < 0.001 by 2-sided, unpaired t test (F) or 1-way ANOVA (I). Scale bars: 20 g (A, vertical); 1 s (A, horizontal).