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

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

Author information

1
Department of Psychology University of Kentucky College of Arts and Sciences Lexington KY USA.
2
Department of Molecular & Cellular Biochemistry University of Kentucky Medical Center Lexington KY USA.
3
Department of Neuroscience University of Kentucky Medical Center Lexington KY USA.
4
Department of Neurology University of Kentucky Medical Center Lexington KY USA.
5
Neurology Service Veterans Affairs Medical Center Lexington KY USA.
6
Department of Pharmacology and Nutritional Sciences University of Kentucky Medical Center Lexington KY USA.

Abstract

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

PMID:
28948088
PMCID:
PMC5607557
DOI:
10.1002/brb3.795
[Indexed for MEDLINE]
Free PMC Article

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