Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

Department of Neurology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, United States.
Epilepsy Research (Impact Factor: 2.02). 06/2008; 79(2-3):213-23. DOI: 10.1016/j.eplepsyres.2008.02.006
Source: PubMed


Acquired epilepsy (AE) is characterized by spontaneous recurrent seizures and long-term changes that occur in surviving neurons following an injury such as status epilepticus (SE). Long-lasting alterations in hippocampal Ca(2+) homeostasis have been observed in both in vivo and in vitro models of AE. One major regulator of Ca(2+) homeostasis is the neuronal calcium binding protein, calbindin-D28k that serves to buffer and transport Ca(2+) ions. This study evaluated the expression of hippocampal calbindin levels in the rat pilocarpine model of AE. Calbindin protein expression was reduced over 50% in the hippocampus in epileptic animals. This decrease was observed in the pyramidal layer of CA1, stratum lucidum of CA3, hilus, and stratum granulosum and stratum moleculare of the dentate gyrus when corrected for cell loss. Furthermore, calbindin levels in individual neurons were also significantly reduced. In addition, the expression of calbindin mRNA was decreased in epileptic animals. Time course studies demonstrated that decreased calbindin expression was initially present 1 month following pilocarpine-induced SE and lasted for up to 2 years after the initial episode of SE. The results indicate that calbindin is essentially permanently decreased in the hippocampus in AE. This decrease in hippocampal calbindin may be a major contributing factor underlying some of the plasticity changes that occur in epileptogenesis and contribute to the alterations in Ca(2+) homeostasis associated with AE.

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    • "In previous studies, decreased CB expression was observed in epileptic conditions13, and some steroids, such as testosterone and estrogen, stimulated CB synthesis.14,15 However, the effect of neurosteroids on CB expression in epilepsy is unclear. "
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    ABSTRACT: Background and Purpose: Neurosteroids exert their antiepileptic effects via GABAA and NMDA receptors. Another cell death mechanism is excessive Ca2+ influx into cells. Calbindin-D28k (CB) is a protein that modulates intracellular Ca2+ in the nervous system. We evaluated whether androsterone up-regulates the expression of CB and has a neuroprotective effect by controlling Ca2+ after pilocarpine-induced status epilepticus (SE) in mice. Methods: SE was induced in ICR mice by injection of pilocarpine. Two hours after SE, mice were treated intraperitoneally (i.p.) with androsterone (100–200 mg/kg) or vehicle, and compared with other control groups. Two days after injection, immunohistochemical staining for CB was performed using a hippocampal slice from each mice group. We also used cresyl violet staining to compare changes in hippocampal structures. Results: Two days after pilocarpine-induced SE, androsterone increased the expression of CB in the hippocampus compared with control SE mice. The number of CB-positive cells was 1±0.4 cells/mm3 in pilocarpine-only group, 14±1.1 cells/mm3 in pilocarpine plus androsterone 100 mg group and 29±2.5 cells/mm3 in pilocarpine plus androsterone 200 mg group (p<0.001). Conclusions: These results suggest that the neuroprotective effect of androsterone after pilocarpine- induced SE may be mediated by an increased expression of CB.
    06/2014; 4(1):7-13. DOI:10.14581/jer.14002
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    • "The pilocarpine-induced seizure is a well-established rodent model of temporal lobe epilepsy 22, 23–25. Based on the previous evidence that there is a permanent reduction of calbindin mRNA and protein expression from the hippocampus of rats following pilocarpine treatment 26, and a similar reduction in human postmortem epileptic brains 27, 28, we anticipated that the pilocarpine-induced seizure mice may also exhibit an iDG phenotype linking the pathophysiology of the two mouse models. "
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    ABSTRACT: Objectives There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Methods Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. Results The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Conclusions Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy and bipolar disorder/schizophrenia are strikingly similar.
    Bipolar Disorders 04/2013; 15(4). DOI:10.1111/bdi.12064 · 4.97 Impact Factor
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    • "However, previous studies have suggested that epilepsy is a candidate for producing the iDG phenotype. A long-term reduction in calbindin mRNA and protein expression has been observed in the hippocampi of rats following pilocarpine treatment [57]. A similar reduction in calbindin has been reported in human epileptic brains examined postmortem [58,59]. "
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    ABSTRACT: Background Synaptosomal-associated protein, 25 kDa (SNAP-25) regulates the exocytosis of neurotransmitters. Growing evidence suggests that SNAP-25 is involved in neuropsychiatric disorders, such as schizophrenia, attention-deficit/hyperactivity disorder, and epilepsy. Recently, increases in anxiety-related behaviors and epilepsy have been observed in SNAP-25 knock-in (KI) mice, which have a single amino acid substitution of Ala for Ser187. However, the molecular and cellular mechanisms underlying the abnormalities in this mutant remain unknown. Results In this study, we found that a significant number of dentate gyrus (DG) granule cells was histologically and electrophysiologically similar to immature DG neurons in the dentate gyrus of the adult mutants, a phenomenon termed the “immature DG” (iDG). SNAP-25 KI mice and other mice possessing the iDG phenotype, i.e., alpha-calcium/calmodulin-dependent protein kinase II heterozygous mice, Schnurri-2 knockout mice, and mice treated with the antidepressant fluoxetine, showed similar molecular expression patterns, with over 100 genes similarly altered. A working memory deficit was also identified in mutant mice during a spontaneous forced alternation task using a modified T-maze, a behavioral task known to be dependent on hippocampal function. Chronic treatments with the antiepileptic drug valproate abolished the iDG phenotype and the working memory deficit in mutants. Conclusions These findings suggest that the substitution of Ala for Ser187 in SNAP-25 induces the iDG phenotype, which can also be caused by epilepsy, and led to a severe working memory deficit. In addition, the iDG phenotype in adulthood is likely an endophenotype for at least a part of some common psychiatric disorders.
    Molecular Brain 03/2013; 6(1):12. DOI:10.1186/1756-6606-6-12 · 4.90 Impact Factor
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