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 2

Syt2 is prominently expressed in cortical PV+ neurons, but deletion of Syt2 from mPFC PV+ neurons does not impair their synaptic releases.

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Syt2 is prominently expressed in cortical PV+ neurons, but deletion of S...
(A and B) Representative images of different coronal brain sections showing the immunostaining of Syt2 for PVcre (A) and PVcre Syt2fl (B) mice. (C and D) Deleting Syt2 from mPFC PV+ neurons did not affect sIPSCs received by pyramidal neurons. (C) Top, differential interference contrast (DIC) and fluorescence images showing the expression of EGFP-Cre in the mPFC of an Syt2fl/fl mouse. Slice is arranged upright; bottom, example traces showing the sIPSCs recorded from mPFC pyramidal neurons with (GFP side) and without (non-GFP side) deletion of Syt2 from PV+ neurons. (D) Summary graph of the sIPSC frequency (left) and amplitude (right) recorded from mPFC pyramidal neurons on GFP and non-GFP sides (n = 10 non-GFP, n = 10 GFP for both frequency and amplitude). (E and F) Deleting Syt2 from mPFC PV+ neurons did not affect evoked IPSCs received by pyramidal neurons. (E) Top, DIC and fluorescence images showing the expression of Cre-dependent CHiEF-tdTomato in mPFC PV+ neurons of a PVcre Syt2fl mouse. Slice is arranged upright; bottom, example traces showing the 1-ms, 45-Hz blue laser–evoked IPSCs (shown as blue vertical bars) recorded from mPFC pyramidal neurons in a PVcre Syt2fl mouse and a control mouse. (F) Summary graph of 45-Hz light–evoked IPSC amplitude (in response to the first 10 train stimuli) recorded from mPFC pyramidal neurons in control and PVcre Syt2fl mice (n = 9 control, n = 7 PVcre Syt2fl). For D and F, data are shown as means ± SEM from at least 3 independent litters. Scale bars: 1 mm (A); 0.5 mm (C, top); 50 pA (C, vertical); 0.5 S (C, bottom horizontal); 0.5 mm (E, top); 0.5 nA (E, vertical); 0.1 s (E, bottom horizontal).