Work

Astrocytic FKBP5 regulates neuroinflammation and cognitive outcomes in male mouse models of excitotoxic epilepsy

Year: 2026

Type: article

Abstract: 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 (a Fkbp5 -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-κB p65 phosphorylation. Notably, overexpression of an Fkbp5 quadruple mutant that disrupts the FKBP51–NF-κB interaction inhibited proinflammatory lipopolysaccharide (LPS)-induced astrogliosis and NF-κB activation. The hippocampal transcriptome of the LPS-treated Fkbp5 -KO mice revealed suppression of NF-κB signaling. In summary, this study highlights FKBP51 as a key mediator of excitotoxin-induced neuroinflammation and GLT-1 dysfunction and underlines NF-κB-mediated inflammatory astrogliosis as a potential intervention target for excitotoxic brain injury.

Source: Brain Behavior and Immunity

DOI: 10.1016/j.bbi.2026.106278