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Persistent Hyperactivity of Hippocampal Dentate Interneurons After a Silent Period in the Rat Pilocarpine Model of Epilepsy.

ABSTRACT: Profile of GABAergic interneuron activity after pilocarpine-induced status epilepticus (SE) was examined in the rat hippocampal dentate gyrus by analyzing immediate early gene expression and recording spontaneous firing at near resting membrane potential (REM). SE for exact 2 h or more than 2 h was induced in the male Sprague-Dawley rats by an intraperitoneal injection of pilocarpine. Expression of immediate early genes (IEGs) was examined at 1 h, 1 week, 2 weeks or more than 10 weeks after SE. For animals to be examined at 1 h after SE, SE lasted for exact 2 h was terminated by an intraperitoneal injection of diazepam. Spontaneous firing at near the REM was recorded in interneurons located along the border between the granule cell layer and the hilus more than 10 weeks after SE. Results showed that both c-fos and activity-regulated cytoskeleton associated protein (Arc) in hilar GABAergic interneurons were up-regulated after SE in a biphasic manner; they were increased at 1 h and more than 2 weeks, but not at 1 week after SE. Ten weeks after SE, nearly 60% of hilar GABAergic cells expressed c-fos. With the exception of calretinin (CR)-positive cells, percentages of hilar neuronal nitric oxide synthase (nNOS)-, neuropeptide Y (NPY)-, parvalbumin (PV)-, and somatostatin (SOM)-positive cells with c-fos expression are significantly higher than those of controls more than 10 weeks after SE. Without the REM to be more depolarizing and changed threshold potential level in SE-induced rats, cell-attached recording revealed that nearly 90% of hilar interneurons fired spontaneously at near the REM while only 22% of the same cell population did so in the controls. In conclusion, pilocarpine-induced SE eventually leads to a state in which surviving dentate GABAergic interneurons become hyperactive with a subtype-dependent manner; this implies that a fragile balance between excitation and inhibition exists in the dentate gyrus and in addition, the activity-dependent up-regulation of IEGs may underlie plastic changes seen in some types of GABAergic cells in the pilocarpine model of epilepsy.

SUBMITTER: Wang X

PROVIDER: S-EPMC4824773 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Persistent Hyperactivity of Hippocampal Dentate Interneurons After a Silent Period in the Rat Pilocarpine Model of Epilepsy.

Wang Xiaochen X Song Xinyu X Wu Lin L Nadler J Victor JV Zhan Ren-Zhi RZ

Frontiers in cellular neuroscience 20160408

Profile of GABAergic interneuron activity after pilocarpine-induced status epilepticus (SE) was examined in the rat hippocampal dentate gyrus by analyzing immediate early gene expression and recording spontaneous firing at near resting membrane potential (REM). SE for exact 2 h or more than 2 h was induced in the male Sprague-Dawley rats by an intraperitoneal injection of pilocarpine. Expression of immediate early genes (IEGs) was examined at 1 h, 1 week, 2 weeks or more than 10 weeks after SE. ...[more]

PMID: 27092056

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Project description:BACKGROUND:Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy. METHODS:Initially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX-1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels. RESULTS:Basal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model. CONCLUSIONS:Changes in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present.

Project description:Altered inhibition is a salient feature of hippocampal network reorganization in epilepsy. Hippocampal pyramidal cells and dentate granule cells show specific reduction in cannabinoid receptor type 1 (CB1R)-sensitive GABAergic inputs in experimental epilepsy. In the dentate gyrus, CB1Rs regulate synaptic release from accommodating interneurons (AC-INs) with adapting firing characteristics and axonal projections in the molecular layer, but not from fast-spiking basket cells (FS-BCs). However, it is not known whether the intrinsic physiology and synaptic inhibition of AC-INs responsible for CB1R-sensitive inhibition is altered in epilepsy. Using the pilocarpine-induced status epilepticus (SE) model of epilepsy, we find that the basic physiological characteristics of AC-INs in epileptic rats are not different from age-matched controls. In paired interneuronal recordings, the amplitude of unitary inhibitory synaptic currents (uIPSCs) between AC-INs doubled after SE. Non-stationary noise analysis revealed that the post-SE strengthening of synapses between AC-INs resulted from an increase in postsynaptic receptors. Baseline synaptic release and CB1R antagonist enhancement of release at synapses between AC-INs were not different between control and post-SE rats. Additionally, uIPSC amplitude in FS-BCs to AC-INs pairs was unchanged after SE indicating input-specific microcircuit alterations in inhibitory inputs to AC-INs. At the network level, AC-INs showed no reduction in spontaneous and miniature inhibitory synaptic current (sIPSC or mIPSC) frequency or amplitude after SE. However, AC-IN mIPSC amplitude was persistently enhanced in post-SE and epileptic rats. CB1R agonist reduced the amplitude and suppressed a greater proportion of sIPSCs in AC-INs from post-SE and epileptic rats demonstrating a novel, cell-type specific increase in CB1R-sensitive inhibition of AC-INs after SE. This unique post-SE strengthening of inhibition between AC-INs could lead to activity-dependent suppression of AC-IN firing and compromise dentate CB1R-sensitive inhibition in epilepsy.

Project description:Ephrin‑B3 is important in the regulation of cell proliferation, differentiation and migration via cell‑cell contact, and can activate the reelin pathway during brain development. However, the effect of ephrin‑B3 on hippocampal neurogenesis and the reelin pathway in epilepsy remains to be fully elucidated. In the present study, the expression of ephrin‑B3 in pilocarpine‑induced status epilepticus (SE) rats was investigated. SYBR Green‑based reverse transcription‑quantitative polymerase chain reaction analysis, immunohistochemical labeling and western blot analysis were used to detect the gene and protein expression levels of ephrin‑B3 and reelin pathway proteins. Immunofluorescence staining of doublecortin (DCX) was utilized to analyze hippocampal neurogenesis. The data revealed that the mRNA and protein expression levels of ephrin‑B3 in the hippocampus decreased during the spontaneous seizure period. Of note, the expression of reelin and its downstream phosphorylation disabled 1 (p‑Dab1) were also notably decreased during the spontaneous seizure period, which showed similar dynamic changes as in the expression of ephrin‑B3. In addition, it was found that the number of DCX‑labeled neuronal progenitor cells was increased in the hippocampus following pilocarpine‑induced SE. To further clarify the role of ephrin‑B3 in neurogenesis and the reelin pathway in epilepsy, an exogenous ephrin‑B3 clustering stimulator, EphB3‑Fc, was infused into the bilateral hippocampus of the rats post‑SE. Following EphB3‑Fc injection, it was found that the expression levels of reelin and p‑Dab1 were significantly increased in the epileptic rats following EphB3‑Fc injection. The number of DCX‑labeled neuronal progenitor cells was reduced in the hippocampus of the epileptic rats. Furthermore, the intensity and frequency of spontaneous recurrent seizures and electroencephalographic seizures were attenuated in the epileptic rats post‑injection. These results demonstrated the critical role of ephrin‑B3 in regulation of the reelin pathway and hippocampal neurogenesis in epilepsy, providing experimental evidence that ephrin‑B3 functions as a potential protective factor in epilepsy, at least in animals.

Dataset Information

Persistent Hyperactivity of Hippocampal Dentate Interneurons After a Silent Period in the Rat Pilocarpine Model of Epilepsy.

Publications

Persistent Hyperactivity of Hippocampal Dentate Interneurons After a Silent Period in the Rat Pilocarpine Model of Epilepsy.

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