Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn-1 gene

Brain Behav. 2017 Aug 13;7(9):e00795. doi: 10.1002/brb3.795. eCollection 2017 Sep.


Introduction: In kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn-1, in kindling.

Methods: Stimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild-type and STXBP5/tomosyn-1-/- (Tom-/-) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate-selective microelectrode array (MEA).

Results: Naïve Tom-/- mice had significant increases in KCl-evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom-/- mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom+/+ and Tom-/- mice showed significant increases in KCl-evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom-/- mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom-/- mice.

Conclusions: Our studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn-1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn-1. Loss of this "braking" effect of STXBP5/tomosyn-1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.

Keywords: SNAREs; SV2; epileptogenesis; microelectrode; synaptopathies.

MeSH terms

  • Animals
  • Dentate Gyrus / metabolism*
  • Electric Stimulation / methods
  • Glutamic Acid* / metabolism
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Kindling, Neurologic / metabolism*
  • Male
  • Mice
  • Models, Animal
  • Nerve Tissue Proteins / metabolism*
  • R-SNARE Proteins / metabolism*
  • Synaptic Transmission


  • Nerve Tissue Proteins
  • R-SNARE Proteins
  • tomosyn protein, mouse
  • Glutamic Acid