This study was conducted to characterize the post-pubertal developmental aspects on seizure susceptibility and severity as well as calcium/calmodulin protein kinase type II (CaM kinase II) activity in status epilepticus (SE). Thirty- to ninety-day-old rats, in 10-day increments, were studied. This corresponds to a developmental age group that has not received thorough attention. The pilocarpine model of SE was characterized both behaviorally and electrographically. Seven criteria were analyzed for electrographical characterization: seizure severity, SE susceptibility, the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death. After 1 h of SE, specific brain regions were isolated for biochemical study. Phosphate incorporation into a CaM kinase II-specific substrate, autocamtide III, was used to determine kinase activity. There was no developmental effect on the average number of discrete seizures, average time until first seizure, average time to SE, average time from first discrete seizure to SE, and death; however, there was a significant effect on SE probability and seizure severity. Once SE was expressed, all animals showed a decrease in both cortical and hippocampal CaM kinase II activities. Conversely, seizure activity in the absence of SE did not result in a decrease in CaM kinase II activity. The data suggest that there is a gradual age-dependent modulation of SE susceptibility and seizure severity within the developmental stages studied. Additionally, once status epilepticus is observed at any age, there is a corresponding SE-induced inhibition of CaM kinase II.
"In pilocarpine-treated mice, SRS is an essential requirement for the development of the dematured DG, since mice from our earlier pilot studies that exhibited very mild SE, with no subsequent SRS, failed to induce a dematured phenotype. Additionally, it was also reported that animals that failed to fully develop SE showed no decrease in CaMKII activity 57. These results suggest a strong connection between SRS, dematured DG and CaMKII. "
[Show abstract][Hide abstract] 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.
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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: As a major inhibitory neurotransmitter, GABA plays a vital role in the brain by controlling the extent of neuronal excitation. This widespread role is reflected by the ubiquitous distribution of GABA(A) receptors throughout the central nervous system. To regulate the level of neuronal inhibition requires some endogenous control over the release of GABA and/or its postsynaptic response. In this context, Ca(2+) ions are often used as primary or secondary messengers frequently resulting in the activation of protein kinases and phosphatases. One such kinase, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), can target the GABA(A) receptor to cause its phosphorylation. Evidence is now emerging, which is reviewed here, that GABA(A) receptors are indeed substrates for CaMKII and that this covalent modification alters the expression of cell surface receptors and their function. This type of regulation can also feature at inhibitory synapses leading to long-term inhibitory synaptic plasticity. Most recently, CaMKII has now been proposed to differentially phosphorylate particular isoforms of GABA(A) receptors in a synapse-specific context.
The Journal of Physiology 04/2009; 587(Pt 10):2115-25. DOI:10.1113/jphysiol.2009.171603 · 5.04 Impact Factor
Varun Kumar Sharma, Anaita Udwadia Hegde, Fazal Nabi
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