title: Compromised GABAergic inhibition contributes to tumor-associated epilepsy.
abstract: Glioblastoma Multiforme (GBM) is the most common form of primary brain tumor with 30-50% of patients presenting with epilepsy. These tumor-associated seizures are often resistant to traditional antiepileptic drug treatment and persist after tumor resection. This suggests that changes in the peritumoral tissue underpin epileptogenesis. It is known that glioma cells extrude pathological concentrations of glutamate which is thought to play a role in tumor progression and the development of epilepsy. Given that pathological concentrations of glutamate have been shown to dephosphorylate and downregulate the potassium chloride cotransporter KCC2, we hypothesized that glioma-induced alterations in KCC2 in the peritumoral region may play a role in tumor-associated epilepsy. Consistent with this hypothesis, we observe a decrease in total KCC2 expression and a dephosphorylation of KCC2 at residue Ser940 in a glioma model which exhibits hyperexcitability and the development of spontaneous seizures. To determine whether the reduction of KCC2 could potentially contribute to tumor-associated epilepsy, we generated mice with a focal knockdown of KCC2 by injecting AAV2-Cre-GFP into the cortex of floxed KCC2 mice. The AAV2-Cre-mediated knockdown of KCC2 was sufficient to induce the development of spontaneous seizures. Further, blocking NKCC1 with bumetanide to offset the loss of KCC2 reduced the seizure susceptibility in glioma-implanted mice. These findings support a mechanism of tumor-associated epilepsy involving downregulation of KCC2 in the peritumoral region leading to compromised GABAergic inhibition and suggest that modulating chloride homeostasis may be useful for seizure control.
authors: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States.
authors: Georgina
authors: G
authors: MacKenzie
authors: Training in Education and Critical Research Skills (TEACRS) Program, Tufts University School of Medicine, Boston, MA 02111, United States.
authors: Kate K
authors: KK
authors: O'Toole
authors: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States.
authors: Stephen J
authors: SJ
authors: Moss
authors: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, United States. Electronic address: Jamie.Maguire@tufts.edu.
authors: Jamie
authors: J
authors: Maguire
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000150:complications / Q000378:metabolism*; D002034:Bumetanide / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000637:transplantation; D004195:Disease Models, Animal; D004827:Epilepsy / Q000150:complications / Q000378:metabolism*; D005910:Glioma / Q000150:complications / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D010766:Phosphorylation; D051381:Rats; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D002034:Bumetanide; D018698:Glutamic Acid; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578878:Slc12a2 protein, mouse
keywords: Epilepsy; GABA; Glioma; KCC2; Seizures; Tumor