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

ABSTRACT: FK506-binding protein 51 (FKBP51, encoded by FKBP5) is a multisignaling cochaperone that regulates cellular stress responses and inflammatory signaling through the NF-κB pathway. Although FKBP51 is upregulated in reactive astrocytes, its role in epilepsy and excitotoxic neuroinflammation remains unknown. Excessive astrogliosis and impaired glutamate transporter-1 (GLT-1)-mediated glutamate clearance promote excitotoxicity and increase seizure susceptibility. Here, we investigated how both global and astrocyte-specific Fkbp5 deletions 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 GLT-1 expression in hippocampal CA3. Glia-neuron mixed cultures derived from Fkbp5-KO brains showed reduced NMDA-induced neurotoxicity and 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-induced astrogliosis and NF-κB activation. Transcriptomic analysis of Fkbp5-KO hippocampi further confirmed suppression of NF-κB-driven inflammatory pathways. In summary, astrocytic FKBP51 mediates reactive astrogliosis and GLT-1 downregulation, linking excitotoxic neuroinflammation with seizure susceptibility and cognitive impairment, and represents a potential intervention target for epilepsy.

ORGANISM(S): Mus musculus

PROVIDER: GSE293536 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:The ketogenic diet (KD) is an established treatment for patients with medically intractable epilepsy and is chiefly characterized by the production of ketone bodies (KB) such as β-hydroxybutyrate (BHB). However, after more than a century of clinical use, the mechanisms underlying its efficacy remain unclear. While prior investigations have examined the effects of the KD and its metabolic substrates on synaptic transmission, few studies have explored a potential connection between astrocytic ion channels and seizure genesis. One essential function of astrocytes is spatial potassium buffering which influences passive potassium conductance (PPC), and when impaired, can result in neuronal hyperexcitability. In the present study, we demonstrate that the KD can mitigate hippocampal astrogliosis in the Kcna1-null (KO) mouse model of developmental epilepsy. Specifically, we observed a significant increase in GFAP expression in KO mice fed a control diet compared to wild-type (WT) animals, and that the KD prevented this change. Furthermore, we noted a reduction in hippocampal astrocytic PPC in epileptic mice, whereas KD-treated KO animals exhibited nearly normal passive conductance levels. In this regard, we also provide evidence for the role of Kir4.1 channels in mediating astrocytic PPC, and the activation of these inwardly rectifying potassium channels by BHB. To further explore these findings at a molecular level, we conducted bulk RNA-seq analysis which revealed down-regulation of factors linked to hippocampal astrogliosis, notably those involved with neuroinflammation, consistent with earlier reports highlighting the anti-inflammatory effects of the KD and its metabolic substrates such as BHB. Our findings indicate that the KD protects against epilepsy-associated astrogliosis and astrocytic PPC changes, underscoring a novel mechanism of KD action, and the potential functional role of extracellular potassium in neuronal-glial interactions in the epileptic brain.

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

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