# KCC2 and Spinal Cord Injury

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $420,175

## Abstract

Abstract/Project Summary
Most human spinal cord injuries (SCIs) are anatomically incomplete, with spared axons spanning the
damaged spinal segments. However, about a half of these patients have a total loss of muscle control and
sensation below the injury level. An important but under-studied question is why such spared connections
fail to mediate functional recovery in these cases. Recent advances in human studies show that epidural
stimulation combined with rehabilitative training allows some chronically paralyzed patients with SCI to
regain voluntary movement, highlights the feasibility of reactivating such dormant spinal circuitry. However,
the limited functional recovery only occurs when the stimulation is on. Thus, understanding why this spared
spinal circuitry is dysfunctional after SCI, and how it can best be reactivated, should provide key insights
into developing novel functional restoration strategies for SCI. In mice with staggered bilateral hemisections,
in which the lumbar spinal cord is deprived of all direct brain-derived innervation but dormant relay circuits
remain between the damaged segments, we discovered that systematic treatment with a KCC2 agonist, or
over-expression of KCC2, is able to restore stepping ability in these paralyzed mice. We showed that such
manipulations are able to correct over-inhibition within the spinal relay zone, allowing this detour circuit to
transmit the brain-derived commands to the hindlimb motor command center in the lumbar spinal cord,
leading to functional recovery. With these exciting preliminary results, this proposed study will address
several related questions: what is the mechanism underlying injury-induced KCC2 down-regulation in
injured spinal cord? Why the achieved functional recovery is partial and how to further enhance such
functional recovery? What are the effects of these circuit-modifying treatments in more clinically relevant
injury models, namely severe contusion models?

## Key facts

- **NIH application ID:** 10352309
- **Project number:** 5R01NS110850-04
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** ZHIGANG HE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $420,175
- **Award type:** 5
- **Project period:** 2019-03-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10352309

## Citation

> US National Institutes of Health, RePORTER application 10352309, KCC2 and Spinal Cord Injury (5R01NS110850-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10352309. Licensed CC0.

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