# Impairment of Spinal Development in Cerebral Palsy

> **NIH NIH R01** · UNIVERSITY OF RHODE ISLAND · 2020 · $306,320

## Abstract

Cerebral palsy (CP) is caused by a variety of factors that result in brain damage and permanently impair motor
control, marked by muscle stiffness and spasticity. Despite the seriousness and prevalence (1 in every 400
births), there have been few advancements in therapeutics in recent decades, with most treatments focusing
on symptoms after they emerge rather than prevention and reduction of damage. This may be due to the
historic lack of an animal model that displays a prominent CP-like phenotype in which it is possible to study the
specific mechanisms giving rise to motor impairments. In this project, we propose parallel longitudinal studies
in children with CP and in a new, clinically relevant animal model of CP. Rabbits subjected to prenatal hypoxia-
ischemia (HI) show clear motor symptoms of spasticity associated with CP, most notably muscle stiffness in
the limbs, hypertonia and hyperreflexia. Our main goal is to exploit this animal model to directly investigate
perturbations in the normal development of spinal neurons and neuronal circuits, while relating cellular
changes to motor behavior in both children and young rabbits with and without CP and HI injuries. While
damage to the brain and corticospinal tracts have been the focus of much previous research, aberrant
development of spinal circuits in CP provides a more accessible target for treatment and therapy of motor
dysfunction. After injuries that can cause CP, we know from previous studies in both rabbit and rodent models
that 1) there is altered expression of the Cl- transporter, KCC2 in the brain, and 2) spinal levels of serotonin are
increased. Both of these factors are tightly developmentally regulated, and could directly promote sustained
MN activity when unregulated: 1) with increasing KCC2 expression during development, inhibitory interneurons
in the spinal cord switch from a depolarizing to a hyperpolarizing postsynaptic effect; and 2) development of
persistent inward currents (PICs) may alter intrinsic excitability of motoneurons (MNs). PICs increase neuronal
excitability and sustain firing, but synaptic inhibition is very effective at turning them off. Hence, with loss of
appropriate KCC2 expression, PICs are poised to exert an even greater influence on MN behavior. Our
overarching hypothesis is that injuries causing cerebral palsy alter the development of spinal
excitability in both children and an animal model, including progressive changes in MN PICs and KCC2
expression, in addition to the damage caused to the brain and the descending projections. Along with the
well-documented loss of descending inhibitory tone, enhanced excitability in spinal MNs and reduced efficacy
of spinal inhibitory synapses could contribute to hypertonia and spasticity of patients with cerebral palsy and
these properties could be targeted for treatment.

## Key facts

- **NIH application ID:** 9966047
- **Project number:** 5R01NS104436-04
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Katharina Ann Quinlan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $306,320
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9966047

## Citation

> US National Institutes of Health, RePORTER application 9966047, Impairment of Spinal Development in Cerebral Palsy (5R01NS104436-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9966047. Licensed CC0.

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