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Updated: Apr 26, 2026

Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting
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Study of the Functions and Activities of Neuronal K-Cl Co-Transporter KCC2 Using Western Blotting

Published on: December 9, 2022

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GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy

Susan L Campbell1, Stefanie Robel, Vishnu A Cuddapah

  • 1Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Glia
|July 29, 2014
PubMed

Insights

Glioma-associated seizures involve reduced GABAergic inhibition due to decreased KCC2 expression, leading to neuronal hyperexcitability. This GABAergic disinhibition, alongside glutamate release, drives epilepsy, suggesting KCC2 as a therapeutic target.

Area of Science:

  • Neuroscience
  • Oncology
  • Epileptology

Background:

  • Seizures are common in gliomas, leading to peritumoral epilepsy.
  • Tumor-derived glutamate release via the cystine-glutamate transporter (SXC) is implicated in epileptogenesis.
  • A novel contribution of GABAergic disinhibition to glioma pathophysiology is investigated.

Purpose of the Study:

  • To investigate the role of GABAergic disinhibition in glioma-associated epilepsy.
  • To identify molecular mechanisms underlying altered inhibitory neurotransmission in the peritumoral region.
  • To explore KCC2 as a potential therapeutic target.

Main Methods:

  • Utilized a validated mouse glioma model.
  • Assessed peritumoral parvalbumin-positive GABAergic interneurons.
  • Measured spontaneous and evoked inhibitory neurotransmission.
  • Quantified intracellular chloride concentration ([Cl(-)]i) and KCC2 expression in neurons.

Main Results:

  • Significantly reduced peritumoral GABAergic interneurons and inhibitory neurotransmission.
  • Elevated intracellular chloride concentration ([Cl(-)]i) in remaining neurons, causing depolarizing GABA responses.
  • Decreased plasmalemmal KCC2 expression, impairing chloride extrusion.
  • GABAergic disinhibition was independent of glutamate release but required, with reduced SXC, for epileptogenesis.

Conclusions:

  • GABAergic disinhibition contributes to peritumoral network hyperexcitability in gliomas.
  • Reduced KCC2 expression underlies the excitatory GABA responses and impaired inhibition.
  • Combined GABAergic disinhibition and altered glutamate transport are necessary for glioma-induced epilepsy.
  • KCC2 represents a promising therapeutic target for treating glioma-associated seizures.
Keywords:
GABAKCC2gliomaperitumoral epilepsy

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