Human and Rodent Temporal Lobe Epilepsy is Characterized by Changes in O-GlcNAc Homeostasis that can be Reversed to Dampen Epileptiform Activity

Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-{beta}-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that integrate energy supply with demand. The enzymes O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal, respectively, of the O-GlcNAc modification. The goal of this study was to determine whether changes in OGT/OGA cycling and disruptions in protein O-GlcNAcylation occur in the epileptic hippocampus. We observed reduced global and protein specific O-GlcNAcylation and OGT expression in the kainate rat model of TLE and in human TLE hippocampal tissue. Inhibiting OGA with Thiamet-G elevated protein O-GlcNAcylation, and decreased both seizure duration and epileptic spike events, suggesting that OGA may be a therapeutic target for seizure control. These findings suggest that loss of O-GlcNAc homeostasis in the kainate model and in human TLE can be reversed via targeting of O-GlcNAc related pathways.