Ionic Plasticity: Common Mechanistic Underpinnings of Pathology in Spinal Cord Injury and the Brain

Cells, 2022 · DOI: https://doi.org/10.3390/cells11182910 · Published: September 17, 2022

Spinal Cord Injury Neurology Neuroplasticity

Simple Explanation

GABA normally inhibits neural activity in the adult brain, preventing over-excitation and limiting plasticity. Spinal cord injury can weaken this inhibition in the spinal cord below the injury site. This weakening is linked to reduced levels of a protein called KCC2, which leads to increased chloride inside nerve cells. This reduces the inhibitory effect of GABA, causing over-excitation, contributing to spasticity and chronic pain. Similar KCC2 reductions also contribute to brain-related conditions like epilepsy and addiction. Treatments targeting this 'ionic plasticity' show therapeutic potential.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
Spinal cord injury (SCI) can bring about a modiﬁcation that weakens the inhibitory effect of GABA in the central gray caudal to injury.
2
A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders.
3
Pharmacological treatments that target ionic plasticity have been shown to bring therapeutic beneﬁts.

Research Summary

The neurotransmitter GABA is normally characterized as having an inhibitory effect on neural activity in the adult central nervous system (CNS), which quells over-excitation and limits neural plasticity. Spinal cord injury (SCI) can bring about a modiﬁcation that weakens the inhibitory effect of GABA in the central gray caudal to injury. This change is linked to the downregulation of the potassium/chloride cotransporter (KCC2) and the consequent rise in intracellular Cl−in the postsynaptic neuron. A downregulation of KCC2 also contributes to the development of a number of brain-dependent pathologies linked to states of neural over-excitation, including epilepsy, addiction, and developmental disorders, along with other diseases such as hypertension, asthma, and irritable bowel syndrome.

Practical Implications

New Therapeutic Options

Targeting ionic plasticity may offer new avenues for treating conditions like spasticity, chronic pain, epilepsy, and addiction.

Personalized Medicine

Understanding the role of sex and hormones in ionic plasticity may allow for personalized pain management strategies.

Rehabilitation Strategies

Rehabilitative exercise programs reverse ionic plasticity and restore KCC2, NKCC1, and BDNF levels, which can reduce motor neuron excitability and alleviate the symptoms of spasticity.

Study Limitations

1
Treatments that broadly augment GABAergic inhibition generally have a sedative effect that interferes with function.
2
Drugs that target NKCC1, which is expressed in many tissue types throughout the body, can have adverse secondary effects.
3
The precise circumstances under which targeting ionic plasticity will bring therapeutic beneﬁt need further delineation.

Your Feedback

Was this summary helpful?

Back to Spinal Cord Injury