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

Area of Science:

• Neuroscience
• Molecular Biology
• Epilepsy Research

Background:

• Post-stroke seizures are a significant complication with few treatment options.
• Impaired potassium chloride cotransporter 2 (KCC2) activity disrupts chloride homeostasis, driving neuronal hyperexcitability.
• The role of microglial brain-derived neurotrophic factor (BDNF) in KCC2 regulation and seizures post-stroke is unclear.

Purpose of the Study:

• Investigate the role of microglial BDNF/TrkB signaling in KCC2 dysfunction and seizure susceptibility after stroke.
• Identify potential therapeutic targets for preventing or treating early post-stroke seizures.

Main Methods:

• Utilized a middle cerebral artery occlusion-reperfusion (MCAO-R) mouse model and oxygen-glucose deprivation/reoxygenation (OGD/R) in hippocampal neurons.
• Assessed KCC2 function, neuronal excitability, and seizure susceptibility using electrophysiology, EEG, and behavioral tests.
• Employed pharmacological agents including minocycline, K252a, furosemide (FUR), and CLP290 to modulate microglial activity, TrkB signaling, and KCC2 function.

Main Results:

• MCAO-R and OGD/R reduced membrane KCC2 expression, depolarized GABA equilibrium potentials (E_GABA), and increased neuronal excitability.
• Pharmacological KCC2 enhancement (FUR, CLP290) suppressed epileptiform activity and increased seizure thresholds.
• Inhibition of microglia or TrkB restored KCC2 expression, normalized E_GABA, and reduced seizure severity.

Conclusions:

• Microglia-derived BDNF/TrkB signaling critically mediates KCC2 dysfunction in early post-stroke seizures.
• Targeting microglial activation, TrkB signaling, or KCC2 function presents a promising therapeutic strategy for stroke-related epilepsy.