Astrocytic FKBP5 Regulates Neuroinflammation and Cognitive Outcomes in Excitotoxic Brain Injury

FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular responses to stress. FKBP51 is upregulated in reactive astrocytes; however, the role of FKBP51 in excitotoxic brain injury remains unknown. Here, we investigated how both global and astrocyte-specific Fkbp5 deletion influence seizure susceptibility, astrogliosis, neuroinflammation, and cognition in male mice subjected to a kainic acid (KA)-induced epilepsy mouse model. Global Fkbp5 knockout (Fkbp5-KO) presented lower seizure activity along with decreased neuronal loss and astrogliosis in the hippocampus compared with the wild-type mice. Astrocyte-specific Fkbp5 conditional knockout (aFkbp5-cKO) mice similarly attenuated seizure severity, decreased astrogliosis, improved novel object recognition, and preserved glutamate transporter 1 (GLT-1) expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduction of NMDA-induced neurotoxicity, astrogliosis, accompanied by decreased NF-{kappa}B p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51-NF-{kappa}B interaction inhibited proinflammatory lipopolysaccharide (LPS)-induced astrogliosis and NF-{kappa}B activation. The hippocampal transcriptome of the LPS-treated Fkbp5-KO mice revealed suppression of NF-{kappa}B signaling. In summary, this study highlights FKBP51 as a key mediator of excitotoxin-induced neuroinflammation and GLT-1 dysfunction and underlines NF-{kappa}B-mediated inflammatory astrogliosis as a potential intervention target for excitotoxic brain injury.