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Meta-Analysis of Micrornas Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy

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Meta-Analysis of Micrornas Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy New Research Disorders of the Nervous System Meta-Analysis of MicroRNAs Dysregulated in the Hippocampal Dentate Gyrus of Animal Models of Epilepsy ء ء Prashant K. Srivastava,1, Paolo Roncon,2, Katarzyna Lukasiuk,3 Jan A. Gorter,4 Eleonora Aronica,5 Asla † † Pitkänen,6 Enrico Petretto,7 Michael R. Johnson,1, and Michele Simonato2,8,9,10 DOI:http://dx.doi.org/10.1523/ENEURO.0152-17.2017 1Division of Brain Sciences, Imperial College London, Charing Cross Hospital, W12 0NN London, United Kingdom, 2Division of Neuroscience, University Vita-Salute San Raffaele, Milan 20132, Italy, 3Nencki Institute of Experimental Biology, Polish Academy of Sciences, 02-093 Warsaw, Poland, 4Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam, 1105 Amsterdam, The Netherlands, 5Department of (Neuro)Pathology, Academic Medical Center and SEIN – Stichting Epilepsie Instellingen Nederland, The Netherlands, 6Department of Neurobiology, A.I. Virtanen Institute for Molecular Sciences University of Eastern Finland, FIN-70 211 Kuopio, Finland, 7Duke-NUS Medical School, Singapore 169857, Singapore, 8Department of Medical Sciences, Section of Pharmacology, University of Ferrara, Ferrara, Italy, 9National Institute of Neuroscience, Italy, and 10Laboratory for Technologies of Advanced Therapies (LTTA), Ferrara 44121, Italy Abstract The identification of mechanisms transforming normal to seizure-generating tissue after brain injury is key to devel- oping new antiepileptogenic treatments. MicroRNAs (miRNAs) may act as regulators and potential treatment targets for epileptogenesis. Here, we undertook a meta-analysis of changes in miRNA expression in the hippocampal dentate gyrus (DG) following an epileptogenic insult in three epilepsy models. We identified 26 miRNAs significantly differen- tially expressed during epileptogenesis, and five differentially expressed in chronic epilepsy. Of these, 13 were not identified in any of the individual studies. To assess the role of these miRNAs, we predicted their mRNA targets and then filtered the list to include only target genes expressed in DG and negatively correlated with miRNA expression. Functional enrichment analysis of mRNA targets of miRNAs dysregulated during epileptogenesis suggested a role for molecular processes related to inflammation and synaptic function. Our results identify new miRNAs associated with epileptogenesis from existing data, highlighting the utility of meta-analysis in maximizing value from preclinical data. Key words: dentate gyrus; epilepsy; hippocampus; meta-analysis; miRNA; mRNA Significance Statement Meta-analyses of data from human research studies are an invaluable tool, and the methods to conduct these investigations are well established. However, meta-analyses of preclinical data are rarely undertaken, due to the typically small sample sizes and the substantial heterogeneity between studies. We implemented a meta-analysis of microRNA (miRNA) expression changes in animal studies of epilepsy. This is the first study of its kind in the field of epilepsy and one of the first in preclinical research. Our analyses identify new miRNAs associated with epileptogenesis and epilepsy, highlighting common mechanisms across different animal models. These miRNAs and their predicted effects on gene expression generate new hypotheses about the causes of epilepsy that will prompt new studies in the field. Received April 28, 2017; accepted November 22, 2017; First published Authors contributions: P.K.S., P.R., M.R.J., and M.S. performed research; December 13, 2017. E.P., K.L., J.A.G., E.A., and A.P. designed research; P.K.S., P.R., M.R.J., and The authors declare no competing financial interests. M.S. wrote the paper. November/December 2017, 4(6) e0152-17.2017 1–22 New Research 2 of 22 Introduction Interpretation of data investigating the dysregulation of Epilepsy is a serious, common neurologic disorder pri- miRNAs in the brains of patients with epilepsy is chal- marily characterized by the occurrence of spontaneous lenged by the absence of appropriate human control brain seizures. The treatment of epilepsy remains as one of the tissue (Roncon et al., 2016). Research on the role of major unmet medical needs in neurology because, de- miRNAs in epilepsy has therefore focused on the use of spite of over 20 antiepileptic drugs on the market, sei- experimental models of epilepsy, revealing changes in the zures are not controlled in about one third of the patients. expression of hippocampal miRNAs at different stages of The most common form of epilepsy in adults originates in the epileptogenic process (Henshall et al., 2016). How- temporal structures of the brain (temporal lobe epilepsy, ever, methodological differences between the various TLE; Hauser et al., 1993). Epilepsy (TLE in particular) preclinical animal models of epilepsy have made compar- frequently arises as a consequence of brain injury (“ac- isons between studies difficult and the identification of quired epilepsy”). While acquired epilepsies are in princi- common pathways dysregulated in epileptogenesis and ple preventable by the therapeutic targeting of molecular epilepsy problematic. The current preclinical miRNA stud- processes underpinning their development (i.e., antiepi- ies vary in multiple parameters, including brain region leptogenic therapies), there are currently no established analyzed, animal model, sample size, microarray platform treatment options for halting the transformation of normal and analysis technique. Moreover, these studies are gen- brain tissue to epileptic (Simonato et al., 2014). Identifi- erally substantially underpowered to reliably detect mod- cation of the mechanisms underlying epileptogenesis est changes in miRNA expression. would therefore facilitate the identification of therapies for One particular concern is that analysis of large brain preventing the development of epilepsy and may inform regions (like the hippocampus or the cortex) across dif- new strategies for overcoming drug resistance in epilepsy ferent studies may confound interpretation and compari- more generally (Simonato et al., 2012; 2013; 2014). son because of variable cellular composition (e.g., relating Recent studies have suggested that microRNAs to variable neuronal loss, astrocytosis, microgliosis, etc.). (miRNAs) play an important role in the pathogenesis of One way to address this issue could be to focus on a acquired epilepsy and may represent novel therapeutic specific cell population. In this respect, dentate gyrus targets (Jimenez-Mateos et al., 2012; Brennan et al., (DG) granule cells (GCs) seem particularly attractive as a 2016; for review, see Cattani et al., 2016; Henshall et al., target of analysis as the DG GC layer is a compact layer of 2016). miRNAs are a family of small (21-25 nucleotides) (almost) identical cells, facilitating the dissection of a noncoding RNAs, which can modulate various cellular nearly pure cell population (GCs). Moreover, the DG has and biological processes by degrading or repressing been traditionally described as a “gate” to inhibit hip- translation of specific mRNAs (Bartel, 2004, Guo et al., pocampal overexcitation (Chevaleyre and Siegelbaum, 2010). In systems analysis, miRNAs and their gene targets 2010) and recently, this hypothesis found support from are described as following a “many-to-many” data model, new technologies; optogenetic GC hyperpolarization was such that each miRNA may regulate many transcripts and found to stop spontaneous seizures, whereas optoge- a single transcript may be regulated by many miRNAs netic GC activation exacerbated spontaneous seizures, (Ebert and Sharp, 2012). miRNAs have been implicated in and activating GCs in nonepileptic animals evoked acute various neuronal functions that are relevant in the patho- seizures (Krook-Magnuson et al., 2015). Finally, the DG is genesis of neurologic diseases, including epilepsy (Tan known to undergo important functional changes during et al., 2013; Rajman et al., 2017; for review, see Karnati epileptogenesis (neurogenesis, mossy fiber sprouting, in- et al., 2015). creased excitation; Pitkänen and Lukasiuk, 2011). To date, three studies have investigated differential expression of miRNAs in the DG during the epileptogen- This work was supported by funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under Grant Agreement 602102 esis and the chronic phase of epilepsy in rats (Bot et al., (EPITARGET; to M.R.J., M.S., E.P., K.L., E.A., A.P.), the Imperial College 2013; Gorter et al., 2014; Roncon et al., 2015). Each of National Institute for Health Research Biomedical Research Centre Scheme these studies used a different method to trigger epilepto- (M.R.J., E.P.), and the Polish Ministry of Science and Education Grant W19/ genesis: focal electrical stimulation of the lateral nucleus 7.PR/2014 (to K.L.). -P.K.S. and P.R. contributed equally to this work. of the amygdala (Bot et al., 2013); focal electrical stimuء †M.R.J. and M.S. share the position of senior author and Authors who lation of the angular bundle, a major afferent pathway analyzed data are P.K.S., P.R., M.R.J., and M.S. from the entorhinal cortex to the hippocampus (Gorter Acknowledgements: We thank Dr. Ray Dingledine (Emory University, At- et al., 2014); and the systemically administered chemo- lanta, GA) for helpful discussions and for critically reading this manuscript. Correspondence should be addressed to either of the following: Prof. Mi- convulsant pilocarpine (Roncon et al., 2015). Interestingly, chele
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