# Deconstructing Spasticity after Spinal Cord Injury

> **NIH VA I01** · VA CONNECTICUT HEALTHCARE SYSTEM · 2020 · —

## Abstract

The goal of this study is to investigate the cellular and molecular mechanisms underlying spasticity, and
establish the groundwork for future translational studies in the clinic. A majority of US Veterans with SCI
experience clinically significant spasticity, which can disrupt rehabilitation and negatively impact quality-of-life,
e.g., mobility, personal hygiene, intimate relationships (Holtz et al., 2017; Skold et al., 1999; Walter et al.,
2002). Current spasticity management strategies are palliative, and fail to address the underlying cause.
Available treatment options also carry high risk for adverse effects due to non-specific action or long-term use
(Adams et al., 2005; Kheder et al., 2012). A major hurdle facing the development of better treatments for SCI-
induced spasticity is a lack of mechanistic insight into how injury leads to disability.
To advance an evidence-based investigation toward improving spasticity management, we will carry out
experiments with two objectives:
In Objective 1, we will implement conditional knockout studies to understand the mechanistic contribution of
Rac1 specifically in motor neurons and astrocytes to spasticity after SCI. Our previous work demonstrates that
pharmacological inhibitors can block Rac1-regulated dendritic spine remodeling in motor neurons and reduce
spasticity (Bandaru et al., 2015; Zhao et al., 2016). However, our studies thus far have relied upon the use of a
pharmacological Rac1-inhibitor, NSC23766, which precluded our ability to determine the drug’s direct action on
neurons. It is also unclear why NSC23766 rendered only partial restoration of normal reflex output, and dose-
limiting side effects have prevented longer-term treatment. Thus, to clarify the contribution of Rac1 signaling in
neurons and astrocytes, we will use a 1) virally-mediated Cre-Lox system to knockout Rac1 expression in
motor neurons, and 2) transgenic mice lacking Rac1 specifically in astrocytes. Astrocytes are integral to
synaptic plasticity and maintain neuronal hyperexcitability, but have not been studied within the context of
spasticity after SCI. We will use electrophysiological and behavioral tests to measure evoked H-reflex
excitability and spasticity. To control for other changes in motor function, we will also monitor gross locomotor
function. To assess dendritic spine dysgenesis associated with spasticity, and other anatomical changes, we
will perform image analyses in “cleared” spinal cord tissue.
In Objective 2, to establish the groundwork for clinical translation, we will also assess the feasibility of two
translationally-relevant approaches targeting the Rac1-pathway. Specifically, first we will assess the utility of a
viral-based gene therapy “platform” to knockdown Rac1 expression and alleviate spasticity. We have
previously used viral-delivery of custom-made shRNA constructs to effectively target misexpressed proteins
and modify neuropathic pain after injury or disease (Samad et al., 2013; Tan et al., ...

## Key facts

- **NIH application ID:** 9993926
- **Project number:** 5I01RX002969-02
- **Recipient organization:** VA CONNECTICUT HEALTHCARE SYSTEM
- **Principal Investigator:** Andrew Michael Tan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9993926

## Citation

> US National Institutes of Health, RePORTER application 9993926, Deconstructing Spasticity after Spinal Cord Injury (5I01RX002969-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9993926. Licensed CC0.

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