Increased susceptibility to acetylcholine in the entorhinal cortex of pilocarpine-treated rats involves alterations in KCNQ channels

Maslarova, Anna; Salar, Seda; Lapilover, Ezequiel; Friedman, Alon; Veh, Rüdiger W.; Heinemann, Uwe

doi:10.1016/j.nbd.2013.02.016

Cited by 24 publications

(16 citation statements)

References 76 publications

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“…This was not surprising, because these genes included ion channels, neurotransmitter receptors, calcium-dependent effectors, and phosphoenzymes (Pernhorst et al, 2011; Dingledine, 2012; Rodenas-Ruano et al, 2012; Maslarova et al, 2013). …”

Section: Discussionmentioning

confidence: 99%

“…Neuronal properties may change because of genetic mutations in crucial neuronal genes (Meisler and O'Brien, 2012; Oliva et al, 2012; Kingwell, 2013; Papale et al, 2013) or from insult-related alterations of gene expression that affect the levels and function of their products. Whereas altered expression of individual ion channels (Brewster et al, 2002; Khirug et al, 2010; Poolos, 2012; van Loo et al, 2012; Maslarova et al, 2013; Shah et al, 2013), neurotransmitter receptors (Gonzalez et al, 2013; Rojas and Dingledine, 2013), and other cellular components (Zeng et al, 2009; Maroso et al, 2011; Jimenez-Mateos et al, 2012; Liu et al, 2013) have been extensively reported, the nature and mechanisms of the orchestration of these gene expression changes remain unknown: do epilepsy-provoking insults regulate individual genes via distinct cellular pathways? Alternatively, are there clusters of genes that are co-regulated based on specific common properties, and whose altered expression contributes to the generation of ‘epileptic neurons’?…”

Section: Introductionmentioning

confidence: 99%

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The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes

McClelland

Brennan

Dubé

et al. 2014

eLife

122

138

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The mechanisms generating epileptic neuronal networks following insults such as severe seizures are unknown. We have previously shown that interfering with the function of the neuron-restrictive silencer factor (NRSF/REST), an important transcription factor that influences neuronal phenotype, attenuated development of this disorder. In this study, we found that epilepsy-provoking seizures increased the low NRSF levels in mature hippocampus several fold yet surprisingly, provoked repression of only a subset (∼10%) of potential NRSF target genes. Accordingly, the repressed gene-set was rescued when NRSF binding to chromatin was blocked. Unexpectedly, genes selectively repressed by NRSF had mid-range binding frequencies to the repressor, a property that rendered them sensitive to moderate fluctuations of NRSF levels. Genes selectively regulated by NRSF during epileptogenesis coded for ion channels, receptors, and other crucial contributors to neuronal function. Thus, dynamic, selective regulation of NRSF target genes may play a role in influencing neuronal properties in pathological and physiological contexts.DOI: http://dx.doi.org/10.7554/eLife.01267.001

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes

McClelland

Brennan

Dubé

et al. 2014

eLife

122

138

View full text Add to dashboard Cite

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“…Treatment with citicoline for one week not only enhanced acetylcholine concentrations but also increased vesicular acetylcholine transporter (VAChT) and choline transporter (CHT) in the brain (Tayebati et al, 2011). In-vitro exposure of the entorhinal cortex to low concentrations of acetylcholine (ACh) induces muscarinic-dependent seizurelike events (Maslarova et al, 2013). Acetylcholine (ACh) acts in the central nervous system as a neuromodulator that is involved in the generation of theta rhythms in the hippocampus (Teitelbaum et al, 1975;Zimmerman et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Cytidine 5′-diphosphocholine (CDP-choline) adversely effects on pilocarpine seizure-induced hippocampal neuronal death

et al. 2015

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“…the action of both receptor types results in seizure activity (18). In autosomal dominant nocturnal frontal lobe epilepsy, missense mutations in either the nAChRα4 or β2 nicotinic receptor subunits interrupt cholinergic regulation, leading to seizures (19).…”

mentioning

confidence: 99%

“…Numerous genetic epileptic syndromes are hallmarked by cholinergic dysfunctions that control neuronal excitability and seizure threshold (18,20). Therefore, we predicted that miR modulators of cholinergic activities may avoid neuronal hypersynchronization by performing coordinated surveillance over signaling networks that keep synchronized firing in check, and sought miRs that may play functional role(s) in inducing and/or suppressing seizure-related cholinergic signaling by affecting synaptic targets.…”

mentioning

confidence: 99%

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

Bekenstein

Mishra

Milikovsky

et al. 2017

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

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Epilepsy is a common neurological disease, manifested in unprovoked recurrent seizures. Epileptogenesis may develop due to genetic or pharmacological origins or following injury, but it remains unclear how the unaffected brain escapes this susceptibility to seizures. Here, we report that dynamic changes in forebrain micro-RNA (miR)-211 in the mouse brain shift the threshold for spontaneous and pharmacologically induced seizures alongside changes in the cholinergic pathway genes, implicating this miR in the avoidance of seizures. We identified miR-211 as a putative attenuator of cholinergicmediated seizures by intersecting forebrain miR profiles that were Argonaute precipitated, synaptic vesicle target enriched, or differentially expressed under pilocarpine-induced seizures, and validated TGFBR2 and the nicotinic antiinflammatory acetylcholine receptor nAChRa7 as murine and human miR-211 targets, respectively. To explore the link between miR-211 and epilepsy, we engineered dTg-211 mice with doxycycline-suppressible forebrain overexpression of miR-211. These mice reacted to doxycycline exposure by spontaneous electrocorticography-documented nonconvulsive seizures, accompanied by forebrain accumulation of the convulsive seizures mediating miR-134. RNA sequencing demonstrated in doxycycline-treated dTg-211 cortices overrepresentation of synaptic activity, Ca 2+ transmembrane transport, TGFBR2 signaling, and cholinergic synapse pathways. Additionally, a cholinergic dysregulated mouse model overexpressing a miR refractory acetylcholinesterase-R splice variant showed a parallel propensity for convulsions, miR-211 decreases, and miR-134 elevation. Our findings demonstrate that in mice, dynamic miR-211 decreases induce hypersynchronization and nonconvulsive and convulsive seizures, accompanied by expression changes in cholinergic and TGFBR2 pathways as well as in miR-134. Realizing the importance of miR-211 dynamics opens new venues for translational diagnosis of and interference with epilepsy.

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Increased susceptibility to acetylcholine in the entorhinal cortex of pilocarpine-treated rats involves alterations in KCNQ channels

Cited by 24 publications

References 76 publications

The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes

The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes

Cytidine 5′-diphosphocholine (CDP-choline) adversely effects on pilocarpine seizure-induced hippocampal neuronal death

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

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