Abstract
Neither the molecular basis of the pathologic tendency of neuronal circuits to generate spontaneous seizures (epileptogenicity) nor anti-epileptogenic mechanisms that maintain a seizure-free state are well understood. Here, we performed transcriptomic analysis in the intrahippocampal kainate model of temporal lobe epilepsy in rats using both Agilent and Codelink microarray platforms to characterize the epileptic processes. The experimental design allowed subtraction of the confounding effects of the lesion, identification of expression changes associated with epileptogenicity, and genes upregulated by seizures with potential homeostatic anti-epileptogenic effects. Using differential expression analysis, we identified several hundred expression changes in chronic epilepsy, including candidate genes associated with epileptogenicity such as Bdnf and Kcnj13. To analyze these data from a systems perspective, we applied weighted gene co-expression network analysis (WGCNA) to identify groups of co-expressed genes (modules) and their central (hub) genes. One such module contained genes upregulated in the epileptogenic region, including multiple epileptogenicity candidate genes, and was found to be involved the protection of glial cells against oxidative stress, implicating glial oxidative stress in epileptogenicity. Another distinct module corresponded to the effects of chronic seizures and represented changes in neuronal synaptic vesicle trafficking. We found that the network structure and connectivity of one hub gene, Sv2a, showed significant changes between normal and epileptogenic tissue, becoming more highly connected in epileptic brain. Since Sv2a is a target of the antiepileptic levetiracetam, this module may be important in controlling seizure activity. Bioinformatic analysis of this module also revealed a potential mechanism for the observed transcriptional changes via generation of longer alternatively polyadenlyated transcripts through the upregulation of the RNA binding protein HuD. In summary, combining conventional statistical methods and network analysis allowed us to interpret the differentially regulated genes from a systems perspective, yielding new insight into several biological pathways underlying homeostatic anti-epileptogenic effects and epileptogenicity.
Highlights
Epilepsy is a neurological condition with myriad etiologies that is characterized by the recurrence of spontaneous seizures [1]
Phenotypic characterization of seizures We examined an animal model of focal epilepsy in which kainic acid (KA) is injected into the hippocampus of one hemisphere
By controlling for the effects of the initial neurotoxic hippocampal lesion, the study design allowed the identification of gene expression changes associated with epileptogenicity and homeostatic effects induced by seizures
Summary
Epilepsy is a neurological condition with myriad etiologies that is characterized by the recurrence of spontaneous seizures [1]. One of the most common epilepsy sub-types is mesial temporal lobe epilepsy (MTLE), where the epileptogenic region is localized to the temporal lobe [1]. Electrophysiology, and molecular biology have already led to significant understanding of the types of genes and pathways that cause chronic seizures [3]. Discovery of genes and loci associated with focal epilepsies in the temporal lobe promise to provide insight into the etiology of MTLE [4,5]. Genetic factors may modify the development of epilepsy and generation of spontaneous seizures, and understanding the mechanisms by which temporal lobe lesions lead to chronic epilepsy will provide insight into the genetic basis of epileptogenicity and epilepsy susceptibility
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