Abstract
Pathological synaptic plasticity, manifested as ischemic long-term potentiation, drives neuronal hyperexcitability following oxygen-glucose deprivation. While ischemic long-term potentiation (iLTP) is mediated by excessive GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) activity, the molecular mechanisms sustaining this aberrant plasticity remain poorly understood. FK506-binding protein 51 (FKBP51), a stress-related modulator of plasticity, has emerged as a potential regulator; however, its role in iLTP has not yet been explored. Cathodal direct current stimulation (cDCS), known to suppress pathological hyperexcitability, may offer therapeutic modulation of this process. In this study, we demonstrated that oxygen-glucose deprivation (OGD) induces iLTP alongside FKBP51 upregulation and GluN2B surface accumulation. Genetic deletion of FKBP51 or its pharmacological inhibition (SAFit2, 0.5 µM) normalized synaptic strength and GluN2B expression, establishing FKBP51's critical role in maintaining iLTP. Notably, cDCS intervention replicated these protective effects, attenuating both iLTP and FKBP51 elevation. Our findings identify FKBP51 as a key mediator of ischemic synaptic dysfunction and suggest that cDCS may exert its therapeutic effects through FKBP51-dependent regulation of plasticity, thereby offering new targets for the treatment of ischemic brain injury.