Essential tremor (ET) is one of the most common neurological disorders. It is characterized by an action tremor that most commonly affects arms but also other body parts, impacting the life quality of tens of millions of American people. Despite its high prevalence, the underlying neural mechanisms of ET are poorly understood, and as a result, current medications and surgical treatments are of limited effectiveness. The major obstacle to the study of ET etiology is the absence of a genetic animal ET model. The proposed study aims to elucidate the neural mechanisms underlying ET using a novel genetic mouse ET model. Synaptotagmin 2 (Syt2) has been previously characterized as the fast calcium-sensing protein that facilitates synaptic release. Homozygous Syt2 conditional knockout (cKO) mice crossed with parvalbumin (PV)-cre positive mice (referred to as Syt2-PV mice) exhibit specific action tremor behavior and are potentially a great mouse ET model. Combining mouse genetics, mouse behaviors, viral manipulation and circuit tracing techniques, the proposed study will validate Syt2-PV mice as a great ET animal model and utilize Syt2-PV mice to identify the specific brain region, cell type and projection pathway that generate ET-like behavior (aim 1). The identification of neural circuit components underlying ET will allow investigation of the synaptic mechanisms of ET (aim 2), using slice physiology, viral manipulation and optogenetics. These experiments will seek to establish a more faithful mouse ET model, reveal the neural circuit components and synaptic mechanisms underlying ET and shed lights into the therapeutic interventions of ET.

Public Health Relevance

The proposed studies directly investigate the synaptic and circuit mechanisms of essential tremor disease using a novel genetic mouse model. Results from this study will improve our understanding of the neural mechanisms of essential tremor and promise to provide new avenues of treatments. The mouse essential tremor model we developed will also be useful for other mechanistic studies of tremor and screening for drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01NS105155-02
Application #
9612593
Study Section
Neurological Sciences Training Initial Review Group (NST)
Program Officer
Sieber, Beth-Anne
Project Start
2017-12-15
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304