# Targeting cerebellar excitatory synapses for tremor progression

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $429,656

## Abstract

PROJECT SUMMARY/ ABSTRACT
Essential tremor (ET) is the most common movement disorder with 4% of the population over
age of 40. In addition to the high prevalence, ET is also a progressive disorder and tremor
becomes more severe over time, leading to disability. Therapeutic options for ET are far from
satisfactory, and there is no existing therapy can slow down the disease progression to prevent
disability, in part due to an unclear understanding of the disease mechanism. Recent advances
of ET neuropathology and animal models of tremor indicate that cerebellar excitatory synapses
play a role in tremor. Moreover, a recent genome-wide association study (GWAS) has identified
the association of excitatory amino acid type 2 (EAAT2) in ET, providing clues of astrocytic
contribution to excitatory synapses in ET. However, the detailed mechanism how cerebellar
excitatory synapses and astrocytes could influence tremor still remain obscure, which will be
important knowledge to bridge the prior discoveries into therapeutic development. In this
proposal, we will test the hypothesis that excessive cerebellar excitatory synaptic transmission,
modulated by astrocytic EAAT, contribute to PC degeneration and progressive tremor, using
both animal models and postmortem human ET brains. We will determine whether the speed of
tremor progression or PC degenerative changes can be altered by either long-term over-
excitation of cerebellar excitatory synapses (Aim 1) or the manipulation of cerebellar EAAT2
levels (Aim 2) in a novel mouse model of tremor. We will also test whether astrocytic pathology
and related PC pathology could be observed in genuine ET and correlate with tremor severity
by studying structural alterations in postmortem human ET brains (Aim 3). These data will
advance our understanding of cerebellar excitatory synapses in tremor and will provide scientific
basis to develop mechanism-based therapies for ET.

## Key facts

- **NIH application ID:** 10035002
- **Project number:** 1R01NS118179-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Sheng-Han Kuo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,656
- **Award type:** 1
- **Project period:** 2020-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10035002

## Citation

> US National Institutes of Health, RePORTER application 10035002, Targeting cerebellar excitatory synapses for tremor progression (1R01NS118179-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10035002. Licensed CC0.

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