Linking Kindling to Increased Glutamate Release in the Dentate Gyrus of the Hippocampus Through the STXBP5/tomosyn-1 Gene
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.
Digital Object Identifier (DOI)
This work is supported by a Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research & Development Service (to JTS), a grant from DARPA (N66001-09-C-2080; to GAG), and the NIH (HL56652; to SWW).
Batten, Seth R.; Matveeva, Elena A.; Whiteheart, Sidney W.; Vanaman, Thomas C.; Gerhardt, Greg A.; and Slevin, John T., "Linking Kindling to Increased Glutamate Release in the Dentate Gyrus of the Hippocampus Through the STXBP5/tomosyn-1 Gene" (2017). Psychology Faculty Publications. 141.
Genetics Commons, Neurology Commons, Neuroscience and Neurobiology Commons, Psychology Commons
Published in Brain and Behavior, v. 7, issue 9, e00795, p. 1-11.
© 2017 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.