Dysfunction of parvalbumin neurons in the cerebellar nuclei produces an action tremor
Mu Zhou, Maxwell D. Melin, Wei Xu, Thomas C. Südhof
Mu Zhou, Maxwell D. Melin, Wei Xu, Thomas C. Südhof
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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 5

Identification of CBN downstream targets that induce the action tremor.

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Identification of CBN downstream targets that induce the action tremor. ...
(A) Representative images of anterograde tracing experiments of projections from PV+ neurons in the CBN to other brain regions (left, stereotactic injection strategy of AAVs encoding DIO-mCherry into the CBN of PVcre mice; right images, coronal slices arranged in a caudal → rostral direction showing mCherry expression in the indicated brain regions [note that the 3 fluorescence images on the right were overexposed to reveal the axon terminal signals]). (B) Stereotactic injection strategies of AAVs encoding flippase-dependent Cre (Frt-Cre) in the CBN (most left) or both Frt-Cre in the CBN and AAV retro-flippase in the VAL/VM, red nucleus, or GRN of Syt2fl/fl crossed with EYFP reporter (Syt2 Ai3) mice (3 on the right). (C) Representative images showing the expression of EYFP in CBN for each injection experiment depicted in B. (D) Power spectra of force-plate measurements from representative Syt2 Ai3 mice before and after the corresponding injections shown in B and C. (E) Summary graph of the tremor index before and after each injection shown in B (n = 5 Frt-Cre, n = 5 VAL/VM, n = 6 RN, n = 5 GRN). For E, data are shown as means ± SEM from at least 3 independent litters. *P < 0.05 by Mann-Whitney test (E). Scale bars: 1 mm (A); 1 mm (C).