FKBP51 is Involved in Epileptic Seizure by Regulating PSD95 in a PTZ-Induced Epileptic Mouse Model.

Background: Epilepsy, the world's third most prevalent chronic brain disorder, significantly affects patients' quality of life and increases the economic burden on families and society. Previous studies have demonstrated that FK506-binding protein 51 (FKBP51) plays a crucial role in synaptic plasticity. However, FKBP51 exhibits different functions under various physiological and pathological conditions. Our study explored the relationship between FKBP51 and epilepsy and its possible mechanism of action. We also analyzed the expression levels of postsynaptic density-95 (PSD95) and synaptophysin (SYP) in the hippocampus to examine the pathophysiology of epilepsy.

Methods: A chronic epileptic kindling model was established by injecting pentylenetetrazole (PTZ) intraperitoneally, and a spontaneous seizure model was created by injecting kainic acid (KA) into the dentate gyrus using a stereotaxic apparatus. Endogenous FKBP51 expression was inhibited using adeno-associated virus (AAV)-FKBP51-Small hairpin RNAs (shRNA). The expression of FKBP51, PSD95, and SYP in the hippocampus and synaptosomes was measured through western blotting. Golgi staining and electron microscopy were used to examine spines and synaptic structures.

Results: The results showed a significant increase in FKBP51 expression in the hippocampal tissue of the PTZ- and KA-induced epilepsy model groups. Inhibition of FKBP51 expression through AAV-FKBP51-shRNA resulted in a shorter latency and an elevated seizure grade score in mice. Moreover, the suppression of FKBP51 expression enhanced the expression of synaptic plasticity-related proteins, increased the density of dendritic spines, and elevated the quantity of spherical synaptic vesicles in the presynaptic membrane in the hippocampus.

Conclusions: FKBP51 may serve as an endogenous protective factor in epilepsy by regulating the expression of the synaptic plasticity-related protein PSD95, the density of dendritic spines, and the number of synaptic vesicles in the hippocampal CA1.