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Heat-shock reduces the number of granule cells but not of CR cells. Exemplary, high magnifications of CR (green) cells immunostained against Reelin are shown within the dentate suprapyramidal blade under control condition (A) and after heat-shock (B). Prox-1 immunostained granule cells (red) are shown in a control slice (D) and after heat-shock (E). Counts of CR cells within the molecular layer (mol) show comparable cell numbers (C), whereas granule cell counts revealed a significant reduction in all subregions of the dentate granule cell layer (gcl) investigated (F). Boxplots with median, 25% and 75% quartile, minimum, and maximum. n = 27. Asterisks indicate significance for p < 0.05. gcl, granule cell layer; h, hilus. Scale bar: 50 μm.
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Granule cell dispersion (GCD) has been found in the dentate gyrus (dg) of patients with temporal lobe epilepsy (TLE) and a history of febrile seizures but was also recently observed in pediatric patients that did not suffer from epilepsy. This indicates that GCD might not always be disease related, but instead could reflect normal morphological var...
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One characteristic feature of mesial temporal lobe epilepsy is granule cell dispersion (GCD), a pathological widening of the granule cell layer in the dentate gyrus. The loss of the extracellular matrix protein Reelin, an important positional cue for neurons, correlates with GCD formation in MTLE patients and in rodent epilepsy models. Here, we use...
Prolonged febrile seizures (FS) are a risk factor for the development of hippocampal‐associated temporal lobe epilepsy. The dentate gyrus is the major gateway to the hippocampal network and one of the sites in the brain where neurogenesis continues postnatally. Previously, we found that experimental FS increase the survival rate and structural inte...
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... Increasing evidence has been reported that, under HS conditions, the activity of M1 microglia is increased, promoting the production of pro-inflammatory mediators, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), TNF-α and IL-6 (Vezzani and Ruegg 2011; Estes and McAllister 2014;Lyman et al. 2014;Hsuan et al. 2016). Moreover, Weninger et al. found that, in hippocampal slices treated with a heat shock, the number of microglia significantly increased, based on Iba-1 positive staining, when compared with the control group, with an abundant number of actively phagocytic microglia being observed (Weninger et al. 2021). Similar results were reported in the hypothalamus during acute HS (Belity et al. 2022). ...
Heat stress (HS) can cause a series of stress responses, resulting in numerous negative effects on the body, such as the diminished food intake, carcass quality and reproductive capacity. In addition to the negative effects on the peripheral system, HS leads to central nervous system (CNS) disorders given its toll on neuroinflammation. This neuroinflammatory process is mainly mediated by microglia and astrocytes, which are involved in the activation of glial cells and the secretion of cytokines. While the regulation of inflammatory signaling has a close relationship with the expression of heat shock protein 70 (Hsp70), HS-induced neuroinflammation is closely related to the activation of the TLR4/NF-κB pathway. Moreover, oxidative stress and endoplasmic reticulum (ER) stress are key players in the development of neuroinflammation. Chromium (Cr) has been widely shown to have neuroprotective effects in both humans and animals, despite the lack of mechanistic evidence. Evidence has shown that Cr supplementation can increase the levels of insulin-like growth factor 1 (IGF-1), a major neurotrophic factor with anti-inflammatory and antioxidant effects. This review highlights recent advances in the attenuating effects and potential mechanisms of Cr-mediated IGF-1 actions on HS-induced neuroinflammation, providing presently existing evidence supporting the neuroprotective role of Cr.
... In the identification of mRNA expression profiles following FSs described above, glia was activated (Jongbloets et al., 2015). Among these, modulation of microglia in the structure and function of the hippocampus after early-life FSs received much attention (Andoh et al., 2020;Weninger et al., 2021). Massive microgliosis after FSs was found (Weninger et al., 2021). ...
... Among these, modulation of microglia in the structure and function of the hippocampus after early-life FSs received much attention (Andoh et al., 2020;Weninger et al., 2021). Massive microgliosis after FSs was found (Weninger et al., 2021). The microglial expression levels of Iba1 and ED1 (lysosomal markers) and the proportion of microglia with amoeboid morphology increased, indicating that microglia were activated after FSs (Kong et al., 2019). ...
Febrile seizures (FSs) are convulsions caused by a sudden increase in body temperature during a fever. FSs are one of the commonest presentations in young children, occurring in up to 4% of children between the ages of about 6 months and 5 years old. FSs not only endanger children’s health, cause panic and anxiety to families, but also have many adverse consequences. Both clinical and animal studies show that FSs have detrimental effects on neurodevelopment, that cause attention deficit hyperactivity disorder (ADHD), increased susceptibility to epilepsy, hippocampal sclerosis and cognitive decline during adulthood. However, the mechanisms of FSs in developmental abnormalities and disease occurrence during adulthood have not been determined. This article provides an overview of the association of FSs with neurodevelopmental outcomes, outlining both the underlying mechanisms and the possible appropriate clinical biomarkers, from histological changes to cellular molecular mechanisms. The hippocampus is the brain region most significantly altered after FSs, but the motor cortex and subcortical white matter may also be involved in the development disorders induced by FSs. The occurrence of multiple diseases after FSs may share common mechanisms, and the long-term role of inflammation and γ-aminobutyric acid (GABA) system are currently well studied.
... To examine the potential role of fever on the formation of GCD, we established a model wherein OHSCs were subjected to increased temperature (Weninger et al., 2021). In this model, we found that transiently elevated temperature alone caused GCD, and that this phenomenon was not accompanied by changes in the number of Cajal-Retzius cells. ...
... In some experimental animal models and in humans with TLE, GCD has been linked with the loss of reelin-expressing cells. We recently introduced an in vitro heat-shock model (Weninger et al., 2021) wherein subjecting OHSCs to elevated temperatures induced GCD, but no significant reductions in Cajal-Retzius cells were observed after heat-shock. Here, we attempted to trace the causes that might underlie heatshock induced GCD. ...
... Although no change in the number of Cajal-Retzius cells was observed, independent of treatment type, there was a slight increase in the total number of cells in the molecular layer ( Figure 2F) due to heat-shock treatment. In a previous study (Weninger et al., 2021), an increase in the number of microglial cells was observed in the molecular layer following heat-shock. Thus, migrating or dividing microglial cells might account for the observed increase in the number of cells in the ML in the present study. ...
Granule cell dispersion (GCD) has been associated as a pathological feature of temporal lobe epilepsy (TLE). Early-life epileptiform activity such as febrile seizures has been proposed to have a causal link to developing chronic TLE. During postnatal development, the hippocampus may be particularly vulnerable to hyperexcitability-induced insults since neuronal migration and differentiation are still ongoing in the hippocampus. Further, the extracellular matrix (ECM), here in particular the protein reelin, has been implicated in the pathophysiology of GCD. Thus, loss of reelin-expressing cells, Cajal-Retzius cells and subsets of interneurons, may be related to GCD. To study the possible role of febrile seizures, we previously induced GCD in vitro by subjecting hippocampal slice cultures to a transient heat-shock, which was not accompanied by loss of Cajal-Retzius cells. In order to examine the mechanisms involved in heat-shock induced GCD, the present study aimed to determine whether such dispersion could be prevented by blocking cellular electrical activity. Here we show that the extent of heat-shock induced GCD could be significantly reduced by treatment with the sodium channel blocker tetrodotoxin (TTX), suggesting that electrical activity is an important factor involved in heat-shock induced GCD.
... One difference from many other studies is that the study (Roy et al., 2020) examined mainly pediatric specimens. During development, early generated GCs migrate from the hilus of the DG towards the marginal zone (MZ) to their final positions (Förster et al., 2006;Hayashi et al., 2015), so a transient distribution of newborn GCs in the hilus could reflect a natural stage of early postnatal development of the DG, which, conversely, could be rapidly mistaken for pathological GCD (Weninger et al., 2021). Figure 3 illustrates the histological organization of the DG. ...
... In this regard, epileptic states induce the upregulation of endogenous TIMP-1, thereby inhibiting matrix metalloproteinase activity, ultimately resulting in the extracellular accumulation of un-cleaved reelin (Tinnes et al., 2013). In a more recent study, the association between the occurrence of GCD and FS was investigated, and a transient increase in temperature led to the induction of GCD in vitro, accompanied by partial degeneration of GCs, whereas reelinexpressing CR cells were preserved in the ML, although it could not be ruled out that reelin processing was abnormal (Weninger et al., 2021). In the aforementioned publication, the appearance of GCD after temperature elevation was accompanied by severe microgliosis, suggesting an immune response of the tissue, and it was proposed that microglia could serve as markers to distinguish pathological GCD from normal variation (Roy et al., 2020;Weninger et al., 2021). ...
... In a more recent study, the association between the occurrence of GCD and FS was investigated, and a transient increase in temperature led to the induction of GCD in vitro, accompanied by partial degeneration of GCs, whereas reelinexpressing CR cells were preserved in the ML, although it could not be ruled out that reelin processing was abnormal (Weninger et al., 2021). In the aforementioned publication, the appearance of GCD after temperature elevation was accompanied by severe microgliosis, suggesting an immune response of the tissue, and it was proposed that microglia could serve as markers to distinguish pathological GCD from normal variation (Roy et al., 2020;Weninger et al., 2021). Concordant with this, the results of a transcriptome signature study indicate that macrophages and microglia in particular play a critical role in epileptogenesis (Chen et al., 2020). ...
The extracellular matrix (ECM) of the nervous system can be considered as a dynamically adaptable compartment between neuronal cells, in particular neurons and glial cells, that participates in physiological functions of the nervous system. It is mainly composed of carbohydrates and proteins that are secreted by the different kinds of cell types found in the nervous system, in particular neurons and glial cells, but also other cell types, such as pericytes of capillaries, ependymocytes and meningeal cells. ECM molecules participate in developmental processes, synaptic plasticity, neurodegeneration and regenerative processes. As an example, the ECM of the hippocampal formation is involved in degenerative and adaptive processes related to epilepsy. The role of various components of the ECM has been explored extensively. In particular, the ECM protein reelin, well known for orchestrating the formation of neuronal layer formation in the cerebral cortex, is also considered as a player involved in the occurrence of postnatal granule cell dispersion (GCD), a morphologically peculiar feature frequently observed in hippocampal tissue from epileptic patients. Possible causes and consequences of GCD have been studied in various in vivo and in vitro models. The present review discusses different interpretations of GCD and different views on the role of ECM protein reelin in the formation of this morphological peculiarity.
... Interestingly, the hippocampal granule cells address a special role in learning and spatial memories (Szabadics et al., 2010;Vyas and Montgomery, 2016;Hainmueller and Bartos, 2018), and in the present study, we found wearing thin of granule cell layer and cell body atrophy in mouse brain expressing the mutant protein, except for lipofuscin deposit. Although granule cell dispersion has been linked to chronic epilepsy (Weninger et al., 2021), recent studies pointed out that such correlation might result from the sampling bias, tending to be a normal variation in people without epilepsy (Roy et al., 2020). Up to our recent follow-up, the EEG of the affected patient was still normal, and she did not develop a seizure-like attack. ...
Neuronal ceroid lipofuscinosis (NCL) is composed of a group of inherited neurodegenerative diseases, with the hallmark of lipofuscin deposit (a mixture of lipids and proteins with metal materials) inside the lysosomal lumen, which typically emits auto-fluorescence. Adult-onset NCL (ANCL) has been reported to be associated with a mutation in the DNAJC5 gene, including L115R, L116Δ, and the recently identified C124_C133dup mutation. In this study, we reported a novel C128Y mutation in a young Chinese female with ANCL, and this novel mutation caused abnormal palmitoylation and triggered lipofuscin deposits.
