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A systems level, functional genomics analysis of chronic epilepsy.

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.

SUBMITTER: Winden KD

PROVIDER: S-EPMC3114768 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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A systems level, functional genomics analysis of chronic epilepsy.

Winden Kellen D KD Karsten Stanislav L SL Bragin Anatol A Kudo Lili C LC Gehman Lauren L Ruidera Josephine J Geschwind Daniel H DH Engel Jerome J

PloS one 20110614 6

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 ...[more]

PMID: 21695113

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Project description:We evaluated liver transcriptome throughout gestation and early lactation of purebred and crossbred beef cows (Angus, Hereford and their F1 crossbreeds, CR), grazing high or low herbage allowances (HA) of native grasslands (4 and 2.5 kg DM/kg BW annual mean; n = 16) using an Agilent 4x44k bovine array. A total of 4,661 transcripts were affected by days (272 M-bM-^IM-% 2.5-fold difference, FDR M-bM-^IM-$ 0.10) and 47 pathways were altered during winter gestation (-165 to -15 days relative to calving, d). Gluconeogenesis and fatty acid oxidation pathways were substantially upregulated, while cell growth, DNA replication and transcription pathways were downregulated (FDR M-bM-^IM-$ 0.25). We observed only small changes in the liver transcriptome during the early lactation period (+15 to +60 d). A total of 225 genes were differentially expressed (47 M-bM-^IM-% 2-fold difference, FDR M-bM-^IM-$ 0.10) between HA. The majority of those were related to glucose and pyruvate metabolism and were upregulated in high HA, reflecting their better metabolic status. Two genes were upregulated in CR cows, but 148 transcripts (74 M-bM-^IM-% 2-fold change difference, FDR M-bM-^IM-$ 0.10) were affected by the HA and cow genotype interaction. The transcriptional changes observed indicates a complex and previously unrecognized adaptive program in beef cow liver. We report novel candidate genes, metabolic pathways, and regulatory mechanisms, which can be used as targets of future studies. Complete randomized block design with two spatial replications and a factorial arrangement of herbage allowance (HA) and cow genotype (CG). Herbage allowance treatments represented 4 and 2.5 kg DM/kg BW of annual mean (HI and LO, respectively). Four purebred (PU M-bM-^@M-^S Hereford, H and Angus, A) and four crossbred (CR - F1, HA and AH) multiparous pregnant cows (5 to 6 year-old), were evaluated per treatment (HI-CR, HI-PU, LO-CR, and LO-PU) throughout the gestation and lactation period (-165 to +60 days relative to parturition, days). Cows belonged to or were descendants of experimental animals generated as part of a diallel crossbreeding experiment carried out for 10 years at the Experimental Station and were assigned to the same forage allowance (HI or LO) since May 2007 and gestated and lactated one calf every year from 2007 to 2009.

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A systems level, functional genomics analysis of chronic epilepsy.

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A systems level, functional genomics analysis of chronic epilepsy.

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