Abstract
Molecular mechanisms involved in epileptogenesis in the developing brain remain poorly understood. The gene array approach could reveal some of the factors involved by allowing the identification of a broad scale of genes altered by seizures. In this study we used microarray analysis to reveal the gene expression profile of the laser microdissected hippocampal CA1 subregion one week after kainic acid (KA)-induced status epilepticus (SE) in 21-day-old rats, which are developmentally roughly comparable to juvenile children. The gene expression analysis with the Chipster software generated a total of 1592 differently expressed genes in the CA1 subregion of KA-treated rats compared to control rats. The KEGG database revealed that the identified genes were involved in pathways such as oxidative phosporylation (26 genes changed), and long-term potentiation (LTP; 18 genes changed). Also genes involved in Ca2+ homeostasis, gliosis, inflammation, and GABAergic transmission were altered. To validate the microarray results we further examined the protein expression for a subset of selected genes, glial fibrillary protein (GFAP), apolipoprotein E (apo E), cannabinoid type 1 receptor (CB1), Purkinje cell protein 4 (PEP-19), and interleukin 8 receptor (CXCR1), with immunohistochemistry, which confirmed the transcriptome results. Our results showed that SE resulted in no obvious CA1 neuronal loss, and alterations in the expression pattern of several genes during the early epileptogenic phase were comparable to previous gene expression studies of the adult hippocampus of both experimental epileptic animals and patients with temporal lobe epilepsy (TLE). However, some changes seem to occur after SE specifically in the juvenile rat hippocampus. Insight of the SE-induced alterations in gene expression and their related pathways could give us hints for the development of new target-specific antiepileptic drugs that interfere with the progression of the disease in the juvenile age group.
Highlights
Epilepsy, one of the most common neurological disorders affecting up to 1% of the population, is caused by a number of both unknown and known factors such as trauma, hypoxia, postnatal insults, and status epilepticus (SE) [1,2]
In addition to region-specificity, earlier studies indicate that the extent and localization of kainic acid (KA)-induced hippocampal damage is age-specific, the immature rats (,21-day old) having minor or even no obvious damage [6,7,8], while degeneration of CA1 and CA3 pyramidal neurons and hilar interneurons have frequently been documented in adult rats [3,6,9]
The results of these studies suggest that the expression of a number of genes is altered in the adult rat hippocampus after SE induced by KA [13,14], pentylenetetrazol [15], and electrical stimulation [16,17]
Summary
One of the most common neurological disorders affecting up to 1% of the population, is caused by a number of both unknown and known factors such as trauma, hypoxia, postnatal insults, and status epilepticus (SE) [1,2]. The acute seizure-induced excitotoxic insult is known to initiate a process of changes defined as epileptogenesis, which leads to spontaneous seizures, i.e. epilepsy in the majority of adult rats [1,10,11]. In search for factors involved in epileptogenesis in the hippocampus, the gene expression approach using microarrays has recently been successfully applied. The results of these studies suggest that the expression of a number of genes is altered in the adult rat hippocampus after SE induced by KA [13,14], pentylenetetrazol [15], and electrical stimulation [16,17]. To our knowledge, there is only one earlier microarray study focusing on gene expression in normal immature rats (P3) [21], and no earlier studies after experimental SE either in immature or juvenile animals
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