Exposure of the brain to a stressful stimulus that is sub-threshold for permanent injury can temporarily protect against cell death during a subsequent and otherwise damaging insult. One or more brief, non-harmful seizure episode(s) (seizure preconditioning) can dramatically reduce hippocampal damage when given prior to status epilepticus (epileptic tolerance). We recently reported that status epilepticus-induced hippocampal damage in C57BL/6 mice could be reduced by approximately 50% when preceded 24h earlier by a brief, non-injurious generalized seizure induced by 15mg/kg systemic kainic acid (KA). Since other mouse strains might display different vulnerability to either seizure preconditioning or status epilepticus, we investigated whether epileptic tolerance could be acquired in another strain. SJL mice, reported to display greater seizure sensitivity to systemic KA, received intra-amygdala microinjection of KA to trigger status epilepticus. Intracerebral recordings confirmed evoked seizures involved the ipsilateral hippocampus. Status epilepticus produced hippocampal damage which mainly affected the ipsilateral CA3 and hilus; a pattern similar to C57BL/6 mice. The damage extended through the full rostro-caudal extent of the hippocampal formation. Seizure preconditioning using 20mg/kg systemic KA, but not 15mg/kg, significantly reduced hippocampal damage after status epilepticus by 37% in the dorsal hippocampus and by 65% in the ventral hippocampus. These studies suggest status epilepticus induced by intra-amygdala KA in SJL mice models aspects of the pathophysiology of human mesial temporal sclerosis. Moreover, seizure preconditioning effectively produces neuroprotection in SJL mice, further establishing epileptic tolerance as a conserved endogenous neuroprotection paradigm.
"Food and water was available to mice ad libitum. Induction of status epilepticus in SJL wild-type and 14-3-3ζtg mice was performed as previously described . Briefly, mice were anaesthetised with isoflurane and placed in a mouse adapted stereotaxic frame. "
[Show abstract][Hide abstract] ABSTRACT: 14-3-3 proteins are ubiquitous molecular chaperones that are abundantly expressed in the brain where they regulate cell functions including metabolism, the cell cycle and apoptosis. Brain levels of several 14-3-3 isoforms are altered in diseases of the nervous system, including epilepsy. The 14-3-3 zeta (ζ) isoform has been linked to endoplasmic reticulum (ER) function in neurons, with reduced levels provoking ER stress and increasing vulnerability to excitotoxic injury. Here we report that transgenic overexpression of 14-3-3ζ in mice results in selective changes to the unfolded protein response pathway in the hippocampus, including down-regulation of glucose-regulated proteins 78 and 94, activating transcription factors 4 and 6, and Xbp1 splicing. No differences were found between wild-type mice and transgenic mice for levels of other 14-3-3 isoforms or various other 14-3-3 binding proteins. 14-3-3ζ overexpressing mice were potently protected against cell death caused by intracerebroventricular injection of the ER stressor tunicamycin. 14-3-3ζ overexpressing mice were also potently protected against neuronal death caused by prolonged seizures. These studies demonstrate that increased 14-3-3ζ levels protect against ER stress and seizure-damage despite down-regulation of the unfolded protein response. Delivery of 14-3-3ζ may protect against pathologic changes resulting from prolonged or repeated seizures or where injuries provoke ER stress.
PLoS ONE 01/2013; 8(1):e54491. DOI:10.1371/journal.pone.0054491 · 3.23 Impact Factor
"Indeed, resistant rats share similar clinical signs with animals entering the status over the first 10 minutes after kainte injection (Fig. 1B). Such a process of epileptic tolerance has been observed with preconditioning seizures evoked by kainate injections . Resistance to kainate-induced epilepsy has been also observed in immature rats where multiple kainate injections did not cause major hippocampal damage or electrographic seizures . "
[Show abstract][Hide abstract] ABSTRACT: Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72-85% rats). A group of rats were resistant to develop SE (15-28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals' performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency.
PLoS ONE 10/2012; 7(10):e48128. DOI:10.1371/journal.pone.0048128 · 3.23 Impact Factor
"In epilepsy models, brief seizures triggered by chemoconvulsants or electrical stimulation are the preconditioning stimuli, reducing neuronal death caused by a subsequent episode of status epilepticus (SE). For example, non-convulsive seizures elicited by low-dose systemic kainic acid (KA) prevent hippocampal injury by intraamygdala KA-induced SE in C57BL/6 and SJL mice (Hatazaki et al., 2007; Tanaka et al., 2010). In recent years, our understanding of the molecular processes underlying tolerance has been assisted by microarray profiling, which has revealed large-scale, genomic reprogramming of the response to injury (Stenzel-Poore et al., 2007; Johnson and Simon, 2009). "
[Show abstract][Hide abstract] ABSTRACT: Prolonged seizures (status epilepticus) produce pathophysiological changes in the hippocampus that are associated with large-scale, wide-ranging changes in gene expression. Epileptic tolerance is an endogenous program of cell protection that can be activated in the brain by previous exposure to a non-harmful seizure episode before status epilepticus. A major transcriptional feature of tolerance is gene downregulation. Here, through methylation analysis of 34,143 discrete loci representing all annotated CpG islands and promoter regions in the mouse genome, we report the genome-wide DNA methylation changes in the hippocampus after status epilepticus and epileptic tolerance in adult mice. A total of 321 genes showed altered DNA methylation after status epilepticus alone or status epilepticus that followed seizure preconditioning, with >90% of the promoters of these genes undergoing hypomethylation. These profiles included genes not previously associated with epilepsy, such as the polycomb gene Phc2. Differential methylation events generally occurred throughout the genome without bias for a particular chromosomal region, with the exception of a small region of chromosome 4, which was significantly overrepresented with genes hypomethylated after status epilepticus. Surprisingly, only few genes displayed differential hypermethylation in epileptic tolerance. Nevertheless, gene ontology analysis emphasized the majority of differential methylation events between the groups occurred in genes associated with nuclear functions, such as DNA binding and transcriptional regulation. The present study reports select, genome-wide DNA methylation changes after status epilepticus and in epileptic tolerance, which may contribute to regulating the gene expression environment of the seizure-damaged hippocampus.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 02/2012; 32(5):1577-88. DOI:10.1523/JNEUROSCI.5180-11.2012 · 6.34 Impact Factor
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