Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy

Gorter, Jan A.; Vliet, Erwin A. van; Aronica, Eleonora; Breit, Timo M.; Rauwerda, Han; Silva, Fernando H. Lopes da; Wadman, Wytse J.

doi:10.1523/jneurosci.2766-06.2006

Cited by 300 publications

(273 citation statements)

References 99 publications

Supporting

Mentioning

244

Contrasting

Unclassified

Order By: Relevance

“…Supporting this hypothesis, a fraction of granule cells in the sclerotic hippocampus of MTLE patients are hyperexcitable displaying a weak spike frequency adaptation and an enlarged fast afterhyperpolarization (Selke et al, 2006). Furthermore, a recent microarray study revealed variations in the downregulation of Kcnmb4 in CA3 and entorhinal cortex during acute and latent periods after SE (Gorter et al, 2006). Our study focused on the α-pore-forming BK channel subunit instead of other auxiliary subunits but it will be interesting to further explore the role of β4 in acquired MTLE.…”

Section: Discussionmentioning

confidence: 89%

“…Furthermore, the investigation of seizure-related modifications on the expression levels of biologically-relevant molecules such as ion channels, transporters, enzymatic pathways, etc is being considered a promising strategy to uncover molecular mechanisms of epilepsy as well as potential new antiepileptogeneic targets (Aronica and Gorter, 2007;Crino and Becker, 2006;Jamali et al, 2006;Lukasiuk et al, 2006;Majores et al, 2004;Oscarson et al, 2006). For instances, a large number of down-regulated and up-regulated genes were detected using gene expression profiling by the Affymetrix Gene Chip (RAE230A) in samples (total RNA) isolated from CA3 area and entorhinal cortex at different periods (acute, latent and chronic) following electricallyinduced SE (Gorter et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

View full text Add to dashboard Cite

In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

View full text Add to dashboard Cite

show abstract

“…Mice lacking SV2A develop seizures by postnatal day 7 and die (26), demonstrating the importance of SV2A in postnatal brain development and synaptic function. Moreover, SV2A is down-regulated following seizures (36,37), suggesting that miR-485 may participate in a homeostatic response to hyperexcitation during seizure through posttranscriptional regulation of SV2A to reduce neurotransmitter release. More importantly, we found that SV2A knockdown mimicked the morphological effects of the miR-M and SV2A overexpression reversed the effects of the miR-M, supporting a downstream role of this protein in homeostatic synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA regulation of homeostatic synaptic plasticity

Cohen

Lee

Chen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

191

163

View full text Add to dashboard Cite

Homeostatic mechanisms are required to control formation and maintenance of synaptic connections to maintain the general level of neural impulse activity within normal limits. How genes controlling these processes are co-coordinately regulated during homeostatic synaptic plasticity is unknown. MicroRNAs (miRNAs) exert regulatory control over mRNA stability and translation and may contribute to local and activity-dependent posttranscriptional control of synapseassociated mRNAs. However, identifying miRNAs that function through posttranscriptional gene silencing at synapses has remained elusive. Using a bioinformatics screen to identify sequence motifs enriched in the 3′UTR of rapidly destabilized mRNAs, we identified a developmentally and activity-regulated miRNA (miR-485) that controls dendritic spine number and synapse formation in an activitydependent homeostatic manner. We find that many plasticityassociated genes contain predicted miR-485 binding sites and further identify the presynaptic protein SV2A as a target of miR-485. miR-485 negatively regulated dendritic spine density, postsynaptic density 95 (PSD-95) clustering, and surface expression of GluR2. Furthermore, miR-485 overexpression reduced spontaneous synaptic responses and transmitter release, as measured by miniature excitatory postsynaptic current (EPSC) analysis and FM 1-43 staining. SV2A knockdown mimicked the effects of miR-485, and these effects were reversed by SV2A overexpression. Moreover, 5 d of increased synaptic activity induced homeostatic changes in synaptic specializations that were blocked by a miR-485 inhibitor. Our findings reveal a role for this previously uncharacterized miRNA and the presynaptic protein SV2A in homeostatic plasticity and nervous system development, with possible implications in neurological disorders (e.g., Huntington and Alzheimer's disease), where miR-485 has been found to be dysregulated.activity-dependent development | posttranscriptional gene regulation | presynaptic terminal H omeostatic synaptic plasticity is the process of regulating synaptic connections to compensate for changes in levels of impulse activity in neural networks over a time course of days, thus maintaining circuit function within an optimal range (1). This homeostasis limits changes in synaptic strength induced by Hebbian synaptic plasticity (2), compensates for nervous system disorders causing hyper-or hypoexcitability, and adjusts excitability of neural circuits during development. How genes involved in this process are coordinately regulated is unknown.Increasing excitability of hippocampal or cortical neurons in culture using bicuculline (BiC) reduces synaptic strength through both pre-and postsynaptic mechanisms, and decreasing excitability with TTX produces the opposite response (1, 3, 4). Several molecules have been identified that contribute to homeostatic synaptic plasticity over different time scales, including alterations in the α/β Ca 2+ /CaM-dependent kinase II (CaMKII) ratio (5), astrocytic TNF-α release (6), regulation of c...

show abstract

“…Emerging evidence has indicated that synaptic transmission genes, including dynamin 1, also cause epileptic encephalopathies (6 3,4 and CHENHONG LI human and classical experimental epilepsy. According to previous reports, the differentially expressed genes represent several cellular events, including immune response (7), synaptic transmission (6,8), synaptic plasticity (9) and receptor processes (10)(11)(12). These genome-wide profiles have assisted in understanding the complex molecular mechanisms of epilepsy, however, integrative analyses are often capable of providing more detailed biological insight (13).…”

Section: Introductionmentioning

confidence: 99%

Integrative analysis of gene expression associated with epilepsy in human epilepsy and animal models

Chen

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Epilepsy is a severe neuropsychiatric disorder, the cause of which remains to be elucidated. Genome-wide association studies, DNA microarrays and proteomes have been widely applied to identify the candidate genes involved in epileptogenesis, and integrative analyses are often capable of extracting more detailed biological information from the data. In the present study, a total number of 1,065 genes in different animal models were collected to construct an epilepsy candidate gene database. Further analyses suggested that the response to organic substances, the intracellular signaling cascade and neurological system processes were significantly enriched biological processes, and the mitogen-activated protein kinase pathway was identified as a putative epileptogenic signaling pathway. In addition, the five key genes, growth factor receptor bound 2, amyloid β (A4) precursor protein, transforming growth factor-β, vascular endothelial growth factor and cyclin-dependent kinase inhibitor 1, were identified as being critical as central nodes in the protein networks. Reverse transcription-quantitative polymerase chain reaction analysis revealed that these genes were all upregulated at the mRNA level in the epileptic loci compared with the resection margin of tissue samples from the same patients diagnosed with epilepsy. The data mining performed in the present study thus was shown to be a useful tool, which may contribute to obtaining further information on epileptic disorders and delineating the molecular mechanism of the associated genes. IntroductionEpilepsy is one of the most common types of neurological disorder, which is caused by genetic and acquired factors (1). In terms of the genetics of idiopathic epilepsy, it is likely that an increasing number of genes encoding voltage-gated ion channel subunits, channel-associating proteins, neurotransmitters and neuropeptide receptors modify these phenomena in various types of idiopathic human epilepsy and in different animal models (2). Consistent with this hypothesis, it has been suggested that up to 1,000 genes may be involved in the pathogenesis and evolution of epilepsy (3). Identifying the mechanisms, with particular emphasis on candidate genes, is crucial to improve current understanding of epileptogenicity and epilepsy susceptibility.The procedures of gene profiling by genomic, transcriptomic and proteomic analyses may provide a useful tool in identifying candidate genes, which are of importance in epilepsy. A number of genes have been revealed from genome-wide association studies (GWAS) for focal and generalized types of epilepsy (4). De novo mutations in GABA A receptor (GABR)β3 and UDP-N-acetylglucosamine transferase have previously been reported to be associated with epilepsy (5). Emerging evidence has indicated that synaptic transmission genes, including dynamin 1, also cause epileptic encephalopathies (6

show abstract

Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy

Cited by 300 publications

References 99 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

MicroRNA regulation of homeostatic synaptic plasticity

Integrative analysis of gene expression associated with epilepsy in human epilepsy and animal models

Contact Info

Product

Resources

About