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Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups.

ABSTRACT: Status Epilepticus (SE) is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. However, the role of SE in this injury is uncertain. Until now, we have lacked an animal model in which seizures result in neuronal injury in rodent models at ages below postnatal day 12 (P12) unless seizures are combined with inflammatory stressors.We induced SE with high-dose lithium and pilocarpine in P7 rats, which are developmentally close to human neonates. Several EEG measures and O2 saturation were recorded during the 6h following initiation of SE. We assessed neuronal injury at 6 and 24h post-SE onset using Fluoro-Jade B staining (FJB) and caspase-3a immunoreactivity (IR).EEGs showed continuous polyspikes activity for 54.3 ± 6.7 min, while O2 saturation showed no significant hypoxemia. By 24h after SE onset, significant neuronal injury was observed in CA1/subiculum, CA3, dentate gyrus, thalamus, neocortex, amygdala, piriform cortex, lateral entorhinal cortex, hypothalamus, caudate putamen, globus pallidus, ventral pallidum, and nucleus accumbens. At 24h post-SE, caspase-3a IR was significantly increased in CA1/subiculum, thalamus, and neocortex compared to sham, and caspase-3a IR neurons had fragmented nuclei, suggesting that SE triggered an irreversible form of cell injury.In conclusion, we have developed a model of cholinergic SE in P7 rat pups, which combines high survival (69.9% survival at 24h) and widespread brain injury. These studies suggest that the immature brain is vulnerable to severe forms of SE.

SUBMITTER: Torolira D

PROVIDER: S-EPMC4740206 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups.

Torolira Daniel D Suchomelova Lucie L Wasterlain Claude G CG Niquet Jerome J

Epilepsy research 20151112

<h4>Objective</h4>Status Epilepticus (SE) is common in neonates and infants, and is associated with neuronal injury and adverse developmental outcomes. However, the role of SE in this injury is uncertain. Until now, we have lacked an animal model in which seizures result in neuronal injury in rodent models at ages below postnatal day 12 (P12) unless seizures are combined with inflammatory stressors.<h4>Methods</h4>We induced SE with high-dose lithium and pilocarpine in P7 rats, which are develop ...[more]

PMID: 26709882

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Project description:ObjectiveIn vivo studies of epilepsy typically use prolonged status epilepticus to generate recurrent seizures. However, reports on variable status duration have found discrete differences in injury after 40-50 min of seizures, suggesting a pathophysiologic sensitivity to seizure duration. In this report we take a multivariate cluster analysis to study a short duration status epilepticus model using in vivo 7T magnetic resonance spectroscopy (MRS) and histologic evaluation.MethodsThe Hellier Dudek model was applied with 45 min of status epilepticus after which the animals were imaged twice, at 3 days and 3 weeks post-status epilepticus. Single voxel point resolved spectroscopy (PRESS) MRS was used to acquire data from the dentate gyrus and CA3 region of the hippocampus, assessing metabolite ratios to total creatine (tCr). In a subset of animals after the second imaging study, brains were analyzed histologically by Nissl staining.ResultsA hierarchical cluster analysis performed on the 3-day data from 21 kainate-treated animals (dentate gyrus voxel) segregated into two clusters, denoted by KM (more injured, n = 6) and KL (less injured, n = 15). Although there was no difference in kainate dosing or seizure count between them, the metabolic pattern of injury was different. The KM group displayed the largest significant changes in neuronal and glial parameters; the KL group displayed milder but significant changes. At 3 weeks, the KL group returned to normal compared to controls, whereas the KM group persisted with depressed N-acetyl aspartate (NAA)/tCr, glutamate/tCr, and increased inositol/tCr and glutamine/tCr. The classification was also consistent with subsequent histologic patterns at 3 weeks.SignificanceAlthough a short status period might be expected to generate a continuous distribution of metabolic injury, these data show that the short Hellier Dudek model appears to generate two levels of injury. The changes seen in segregated groups persisted into 3 weeks, and can be interpreted according to neuronal and glial biomarkers consistent with histology results.

Project description:Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue-specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation, we employed the unbiased AcetylScan proteomic screen. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only CamK4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain. mRNA expression analysis was performed by microarray in 3-day-old HDAC4 KO pups and WT littermates. Ten samples were analysed for each genotype. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).

Dataset Information

Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups.

Publications

Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups.

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