Seizure-induced gene expression in area CA1 of the mouse hippocampus (original) (raw)
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Neuroscience, 2001
AbstractöIn various chemoconvulsant models of human temporal lobe epilepsy, the induction of epileptogenesis by a prolonged period of continuous seizure activity is accompanied by signi¢cant changes in hippocampal structure. These changes include an increase in neurogenesis within the proliferative subgranular zone (SGZ) of the dentate gyrus and induction of mossy ¢ber sprouting in mature dentate granule cells. As dentate granule cell neurogenesis and axon outgrowth are also hallmarks of hippocampal development, we hypothesized that molecules involved in normal development may also play a role in similar changes associated with epileptogenesis. To begin to test this hypothesis, we have analyzed the expression patterns of multiple members of the basic helix^loop^helix (bHLH) family of transcription factors in both normal and epileptic adult rats. bHLH protein expression has been found recently in dentate granule cells at speci¢c developmental stages, and analysis of developmental models suggests speci¢c neural di¡erentiation functions for these molecules. We show that mRNA expression of all seven bHLH family members examined in this study, as well as the divergent homeobox protein Prox1, is present in the adult. Patterns of expression varied considerably between family members, ranging from the limited expression of Mash1 in the neurogenic SGZ of the dentate gyrus to the scattered, widespread pro¢le of Hes5 throughout the dentate gyrus and the hippocampus proper. Moreover, these varied pro¢les of expression were di¡erentially regulated following status epilepticus, with some increasing (Mash1, Id2), some falling (Hes5, Prox1), and others remaining mostly unchanged (NeuroD/BETA2, NeuroD2/NDRF, Id3, Rath2/ Nex1).
Gene expression changes after seizure preconditioning in the three major hippocampal cell layers
Neurobiology of Disease, 2007
Rodents experience hippocampal damage after status epilepticus (SE) mainly in pyramidal cells while sparing the dentate granule cell layer (DGCL). Hippocampal damage was prevented in rats that had been preconditioned by brief seizures on 2 consecutive days before SE. To identify neuroprotective genes and biochemical pathways changed after preconditioning we compared the effect of preconditioning on gene expression in the CA1 and CA3 pyramidal and DGCLs, harvested by laser capture microscopy. In the DGCL the expression of 632 genes was altered, compared to only 151 and 58 genes in CA1 and CA3 pyramidal cell layers. Most of the differentially expressed genes regulate tissue structure and intra-and extracellular signaling, including neurotransmission. A selective upregulation of energy metabolism transcripts occurred in CA1 pyramidal cells relative to the DGCL. These results reveal a broad transcriptional response of the DGCL to preconditioning, and suggest several mechanisms underlying the neuroprotective effect of preconditioning seizures.
A comparison between different reference genes for expression studies in human hippocampal tissue
Journal of Neuroscience Methods, 2012
The reliability of gene expression studies by mRNA quantification is highly dependent upon several experimental procedures, including the choice of reference genes used for data normalization. In order to contribute to gene expression studies in mesial temporal lobe epilepsy (MTLE) we used microarray data, followed by real time quantitative PCR validation of selected housekeeping genes, to determine the most appropriate reference genes to be used in human hippocampal tissue gene expression studies. Our results unequivocally showed a significant impact of the reference gene chosen for normalization on the overall results of expression studies, clearly demonstrating the importance of adequate validation using stable reference genes. In addition, we found that HPRT, NSE, SDHA and SYP are suitable genes to be used as reference for normalization in expression studies of hippocampal tissue obtained from patients with MTLE.
Seizures-evoked activation of transcription factors
Acta neurobiologiae experimentalis, 1994
Chemically provoked seizures have proved to serve as useful model to investigate long term neuronal responses collectively termed as neuronal plasticity. In particular, rapid, transient activation of immediate early gene expression induced by such chemoconvulsants like pentylenetetrazole (PTZ) and kainic acid (KA) drew a great attention. These genes code for transcription factors, known to influence gene expression, and therefore able to orchestrate genomic responses to extracellular stimuli. In our studies reviewed herein and reported in detail elsewhere, we have investigated PTZ- and KA-dependent activation of a functional feature of transcription factors i.e. their DNA-binding activity. We have found that only AP-1 DNA-binding activity was elevated in the rat hippocampus, entorhinal and sensory cortices 2-6 h after the PTZ administration, and only in the hippocampus and entorhinal cortex at similar times following KA injection. The AP-1 response to PTZ was strikingly enhanced in ...
European Journal of Neuroscience, 2001
It is not known whether NMDA receptor-dependent long-term potentiation (LTP) is mediated by similar molecular mechanisms in different hippocampal areas. To address this question we have investigated changes in immediate early gene and protein expression in two hippocampal sub®elds following the induction of LTP in vivo and in vitro. In granule cells of the dentate gyrus, LTP induced in vivo by tetanic stimulation of the perforant path was followed by strong induction of the immediate early genes (IEGs) Zif268, Arc and Homer. The increase in Zif268 mRNA was accompanied by an increase in protein expression. In contrast, we were unable to detect modulation of the IEGs Zif268, Arc, Homer and HB-GAM following induction of LTP by high-frequency stimulation of the commissural projection to CA1 pyramidal cells in vivo. In this pathway, we also failed to detect modulation of Zif268 protein levels. Zif268, Arc and Homer can be modulated in CA1 pyramidal cells approximately twofold after electroshockinduced maximal seizure, which demonstrates potential responsiveness to electrical stimuli. When LTP was induced in vitro neither CA1 pyramidal cells nor granule cells showed an increase in Zif268, Arc or Homer mRNA. However, in the slice preparation, granule cells have a different transcriptional state as basal IEG levels are elevated. These results establish the existence of sub®eld-speci®c transcriptional responses to LTP-inducing stimulation in the hippocampus of the intact animal, and demonstrate that in area CA1-enhanced transcription of Zif268, Arc and Homer is not required for the induction of late LTP.
European Journal of Neuroscience, 1993
Fos, jun and krox belong to multigene families coding for transcription factors. These cellular immediate early genes (IEGs) are thought to be involved in coupling neuronal excitation to changes of target gene expression. Immunocytochemistry with specific antisera was used to assess regional levels of six IEG-encoded proteins (c-Fos, Fos B, Krox-24, c-Jun, Jun B, Jun D) in the rat forebrain after kainic acid-induced limbic seizures. The results demonstrate a complex spatial pattern of IEG induction and/or suppression in limbic and non-limbic structures. The sequence of induction within hippocampal subpopulations was identical for all IEGs investigated, following the order dentate gyrus, CA1 and CA3, and irrespective of different temporal profiles for individual transcription factors. Since Fos and Jun proteins act via homo- and heterodimer complexes at specific DNA sites, our data imply that the postictal combinatorial changes of these dimers allow a sequential and differential regu...
Genetic Regulation of Gene Expression in the Epileptic Human Hippocampus
Human molecular genetics, 2017
Epilepsy is a serious and common neurological disorder. Expression quantitative loci (eQTL) analysis is a vital aid for the identification and interpretation of disease-risk loci. Many eQTLs operate in a tissue- and condition-specific manner. We have performed the first genome-wide cis-eQTL analysis of human hippocampal tissue to include not only normal (n = 22) but also epileptic (n = 22) samples. We demonstrate that disease-associated variants from an epilepsy GWAS meta-analysis and a febrile seizures (FS) GWAS are significantly more enriched with epilepsy-eQTLs than with normal hippocampal eQTLs from two larger independent published studies. In contrast, GWAS meta-analyses of two other brain diseases associated with hippocampal pathology (Alzheimer's disease and schizophrenia) are more enriched with normal hippocampal eQTLs than with epilepsy-eQTLs. These observations suggest that an eQTL analysis that includes disease-affected brain tissue is advantageous for detecting addit...
Molecular Brain Research, 1991
Kindling is a phenomenon in which brief afterdischarges (ADs) evoked by periodic electrical stimulation of the brain eventually result in generalized clonic motor seizures. Once present, the enhanced sensitivity to electrical stimulation is lifelong. The mechanism by which brief ADs produce this long-lasting effect may involve a change in gene expression. To begin to investigate changes in gene expression that occur during kindling, we used in situ hybridization histochemistry to examine the time course of expression of mRNAs of the immediate early genes (lEGs) c-fos, c-]un, NGFI-A, and c-myc within the dorsal hippocampus of rats following a kindling AD. Three principal findings resulted from this study. First, the expression of all mRNAs except c-myc was siotmificantly increased (P < 0.05) within discrete neuronal populations. Second, the time course of expression of the lEGs differed markedly within the same neuronal population. Third, for a given lEG, the time course and anatomic pattern of expression were strikingly different among different neuronal populations of the hippocampus. The prolonged and distinctly different patterns of lEG expression suggest that target genes are differentially regulated in these neuronal populations for prolonged periods following a kindling AD.