2. Academic Validation
  3. KCC2 Dysfunction Mediated by Microglial BDNF/TrkB Signaling Exacerbates Early Post-Stroke Seizure Susceptibility

KCC2 Dysfunction Mediated by Microglial BDNF/TrkB Signaling Exacerbates Early Post-Stroke Seizure Susceptibility

  • CNS Neurosci Ther. 2026 Feb;32(2):e70795. doi: 10.1002/cns.70795.
Jing Zhou 1 2,  Benjamin H Wang 1,  Jiangning Yu 1,  Guoxiang Wang 1,  Jingyi Cai 1,  Mohan Yu 1,  Kehua Chen 1,  Li Wan 1,  Xu Liu 1,  Zhigang Yang 1,  Yulong Wang 3,  Yun Wang 1
Affiliations

Affiliations

  • 1 Department of Neurosurgery and Neurology, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Biological Science, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 2 Hangzhou Linping District Integrated Traditional Chinese and Western Medicine Hospital, Hangzhou, Zhejiang, China.
  • 3 Department of Rehabilitation, the First Affiliated Hospital of Shenzhen University/Shenzhen Second People's Hospital, Shenzhen, China.
PMID: 41689206 DOI: 10.1002/cns.70795
Abstract

Background: Post-stroke seizures are a common and debilitating complication with limited therapeutic options, underscoring the need to identify novel molecular targets. Disruption of chloride homeostasis via impaired potassium chloride cotransporter 2 (KCC2) activity is a key driver of neuronal hyperexcitability. While microglia are a predominant source of brain-derived neurotrophic factor (BDNF) in the acute phase after brain injury, the role of microglial BDNF and its signaling in KCC2 dysregulation and early post-stroke seizure susceptibility remain poorly defined.

Methods: Using a middle cerebral artery occlusion-reperfusion (MCAO-R) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons, we assessed KCC2 function, neuronal excitability, and seizure susceptibility. Pharmacological tools, including the microglial inhibitor minocycline, the TrkB Antagonist K252a, the loop diuretic furosemide (FUR), repurposed here as a KCC2-stabilizing agent, and the KCC2 activator CLP290, were employed. Techniques included immunofluorescence, Western blotting, patch-clamp electrophysiology, electroencephalography (EEG), and behavioral seizure assessment.

Results: MCAO-R and OGD/R significantly reduced membrane KCC2 expression, leading to a depolarizing shift in the GABA equilibrium potentials (EGABA), diminished GABAergic inhibition, and increased neuronal excitability. Preventing KCC2 downregulation with FUR or CLP290 suppressed epileptiform activity in vitro and increased seizure thresholds in vivo. Ischemia induced robust microglial activation and increased BDNF release. Pharmacological inhibition of microglia (minocycline) or TrkB (K252a) effectively restored KCC2 expression, normalized EGABA, and reduced post-stroke seizure severity.

Conclusion: Our findings identify microglia-derived BDNF/TrkB signaling as a critical upstream pathway mediating KCC2 dysfunction in early post-stroke seizure. Targeting this axis by inhibiting microglial activation, blocking TrkB, or directly enhancing KCC2 function with activators like CLP290 represents a promising therapeutic strategy for stroke-related epilepsy.

Keywords

BDNF; TrkB; chloride homeostasis; ischemic stroke; microglia; potassium‐chloride cotransporter 2; seizures.

Figures
Products