The etiology and pathology of epilepsy remain elusive. We investigated the role of FK506-binding protein 51 (FKBP51, also called FKBP5) in mouse models of excitotoxic brain injury, and its involvement in reactive astrogliosis and NF-κB signaling.

FKBP51 is an important co-chaperone that modulates stress-responsive glucocorticoid receptor activity. Moreover, FKBP51 labels a subpopulation of reactive astrocytes, but its role in astrogliosis and neuronal excitotoxicity is unclear.

We used a kainic acid (KA)-induced excitotoxicity model in Fkbp5 knockout (Fkbp5-KO) and inducible astrocyte-specific conditional knockout (aFkbp5-cKO) mice to assess the effects on seizure severity, neuronal loss, and astrogliosis. The Fkbp5 quadruple mutants that specifically interfere FKBP51 with NF-κB signaling were developed to elucidate the mechanisms of FKBP51 in NMDA-induced excitotoxicity in primary glia-neuron mixed cultures and astrocyte cultures. Transcriptome analysis of hippocampal tissues were examined to understand the influence of FKBP51 in neuroinflammation.

Both the Fkbp5-KO mice and aFkbp5-KO showed reduced seizure activities and hippocampal astrogliosis compared to the wild-type and Fkbp5^fl/fl controls, respectively. Fkbp5-KO glia-neuron mixed cultures exhibited decreased NMDA-induced neurotoxicity and astrogliosis, with significantly reduced NF-κB p65 phosphorylation. The Fkbp5 quadruple mutants successfully attenuated NF-κB activation in lipopolysaccharide (LPS)-stimulated astrocytes. Lastly, the transcriptomics demonstrated NF-κB pathway blockade and neuroinflammatory downregulation in the Fkbp5-KO hippocampi following LPS treatment.

FKBP51 plays a key role in reactive astrogliosis and neuroinflammation via NF-κB signaling in excitotoxic brain injury, suggesting that FKBP51 may serve as a potential therapeutic target.