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

Abstract

IntroductionIn 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.MethodsStimulating 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).ResultsNaïve 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.ConclusionsOur 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.

Increased seizure sensitivity in pregnant mice with genetic knockdown of acid sensing ion channel 2a is associated with impaired hippocampal inflammatory response

“…In a previous study, NMDAR2a was co-expressed with NMDAR2b, and both isoforms were significantly increased in kindled rat hippocampus and temporal lobe epilepsy patients ( Mathern et al, 1998 ). Previous work reported a significant increase in glutamate concentration following seizures; however, this significant increase was observed only after chronic exposure to seizure induction, rather than acute exposure like in the current work ( Kolosowska et al, 2016 ; Batten et al, 2017 ). To our knowledge, our study is the first to report changes in hippocampal synaptosome glutamate-related proteins in pregnant mice following acute seizure exposure.…”

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

“…Our RNA-seq analyses in control subjects showed that different brain regions had unique transcriptional profiles ( Figure S1). Many of the transcripts enriched in DLPFC were significantly related to synaptic vesicle transport (e.g., KIF5C (12,13), STXBP5L (14)), exocytosis (e.g., STX1A (15)), and neurotransmitter release (e.g,. CADPS2 (16), RIMS3 (17)) (Data file S1).…”

Microelectrode Biosensors for in vivo Analysis of Brain Interstitial Fluid

“…For example, it remains unclear whether glutamate that is released from a synapse diffuses to extrasynaptic interstitial fluid, or remains confined in the synaptic cleft due to the rapid action of specific membrane transporters. Transient changes in glutamate extrasynaptic concentrations have been described in the cortex and amygdala using microelectrode biosensors . However, even with the use of highly selective enzymatic biosensors, glutamate spillover from electrically stimulated hippocampal synapses was found to be undetectable .…”