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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\u2010derived neurotrophic factor (BDNF) in the acute phase after brain injury, the role of microglial BDNF and its signaling in KCC2 dysregulation and early post\u2010stroke seizure susceptibility remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using a middle cerebral artery occlusion\u2010reperfusion (MCAO\u2010R) mouse model and oxygen\u2013glucose 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\u2010stabilizing agent, and the KCC2 activator CLP290, were employed. Techniques included immunofluorescence, Western blotting, patch\u2010clamp electrophysiology, electroencephalography (EEG), and behavioral seizure assessment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MCAO\u2010R and OGD\/R significantly reduced membrane KCC2 expression, leading to a depolarizing shift in the GABA equilibrium potentials (\n                      <jats:italic>E<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>GABA<\/jats:italic>\n                      <\/jats:sub>\n                      ), diminished GABAergic inhibition, and increased neuronal excitability. Preventing KCC2 downregulation with FUR or CLP290 suppressed epileptiform activity in\u00a0vitro and increased seizure thresholds in\u00a0vivo. Ischemia induced robust microglial activation and increased BDNF release. Pharmacological inhibition of microglia (minocycline) or TrkB (K252a) effectively restored KCC2 expression, normalized\n                      <jats:italic>E<\/jats:italic>\n                      <jats:sub>\n                        <jats:italic>GABA<\/jats:italic>\n                      <\/jats:sub>\n                      , and reduced post\u2010stroke seizure severity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings identify microglia\u2010derived BDNF\/TrkB signaling as a critical upstream pathway mediating KCC2 dysfunction in early post\u2010stroke 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\u2010related epilepsy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cns.70795","type":"journal-article","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T05:32:01Z","timestamp":1771047121000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>KCC2<\/scp>\n                    Dysfunction Mediated by Microglial\n                    <scp>BDNF<\/scp>\n                    \/\n                    <scp>TrkB<\/scp>\n                    Signaling Exacerbates Early Post\u2010Stroke Seizure Susceptibility"],"prefix":"10.1002","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7838-4831","authenticated-orcid":false,"given":"Jing","family":"Zhou","sequence":"first","affiliation":[{"name":"Department 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