ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1645428
KCC2 inhibition and neuronal hyperexcitability promote extrinsic apoptosis dependent upon C1q
Provisionally accepted
- Tufts University, Medford, United States
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The potassium chloride co-transporter 2 (KCC2) is the principal Cl -extrusion mechanism employed by mature neurons in the central nervous system (CNS) and plays a critical role in determining the efficacy of fast synaptic inhibition mediated by type A g-aminobutyric acid receptors (GABAARs) to protect against epileptogenesis. It has previously been demonstrated that epileptic seizures down-regulate KCC2 and induce neuronal apoptosis through the extrinsic apoptotic pathway. However, the mechanism by which neuronal death is induced by KCC2 loss remains unknown. We have previously demonstrated that C1q copurifies with KCC2 in comparable amounts. C1q is responsible for synaptic elimination in the brain during development, aging and neurodegeneration. This study demonstrates in vitro, ex vivo and following seizures in vivo, that reduced KCC2 function coincides with neuronal death by activating the extrinsic apoptotic pathway, which is contingent upon complement C1q. Moreover, kainic acid (KA)-and glutamate-induced excitotoxicity also selectively activates the extrinsic apoptotic pathway which is contingent upon C1q. These results strongly support the hypothesis that the KCC2/C1q protein complex plays a critical role in the apoptotic process that occurs following loss of KCC2 function.
Keywords: neuroimmunology, Epilepsy, Apoptosis, potassium chloride co-transporter 2, Complement C1q
Received: 11 Jun 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Ji, Choi, Bope, Dengler, Moss and Smalley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Joshua Luke Smalley, Tufts University, Medford, United States
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