Human and rodent temporal lobe epilepsy is characterized by changes in O-GlcNAc homeostasis that can be reversed to dampen epileptiform activity

Neurobiol Dis. 2019 Apr;124:531-543. doi: 10.1016/j.nbd.2019.01.001. Epub 2019 Jan 6.


Temporal Lobe Epilepsy (TLE) is frequently associated with changes in protein composition and post-translational modifications (PTM) that exacerbate the disorder. O-linked-β-N-acetyl glucosamine (O-GlcNAc) is a PTM occurring at serine/threonine residues that is derived from and closely associated with metabolic substrates. 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 characterize OGT/OGA and protein O-GlcNAcylation in the epileptic hippocampus and to determine and whether direct manipulation of these proteins and PTM's alter epileptiform activity. 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.

Keywords: Electroencephalogram; Electrophysiology; Hippocampus; Magnetic resonance imaging; Mass spectrometry; O-GlcNAcylation; Post-translational modification; Thiamet-G.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Epilepsy, Temporal Lobe / metabolism*
  • Glucosamine / metabolism*
  • Hippocampus / metabolism*
  • Histone Acetyltransferases / metabolism
  • Homeostasis / physiology*
  • Humans
  • Male
  • N-Acetylglucosaminyltransferases / metabolism
  • Protein Processing, Post-Translational / physiology*
  • Rats
  • Rats, Sprague-Dawley


  • Histone Acetyltransferases
  • N-Acetylglucosaminyltransferases
  • UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase
  • Glucosamine