Seizures result from hypersynchronous, abnormal firing of neuronal populations and are the primary clinical symptom of the epilepsies. Brain tissue from animal models and patients with acquired forms of epilepsy commonly features selective neuronal loss, gliosis, inflammatory markers and microscopic and macroscopic reorganization of networks. The gene expression landscape is a critical driver of these changes, and gene expression is fine tuned by small, non-coding RNAs called microRNAs (miRNAs). miRNAs inhibit the function of protein-coding transcripts, resulting in changes in multiple aspects of cell structure and function, including axonal and dendritic structure and the repertoire of neurotransmitter receptors, ion channels and transporters that establish neurophysiological functions. Dysregulation of the miRNA system has emerged as a mechanism that underlies epileptogenesis. Given that miRNAs can act on multiple mRNA targets, their manipulation offers a novel, multi-targeting approach to correct disturbed gene expression patterns. Targeting of some miRNAs has also been used to selectively upregulate individual transcripts, offering the possibility of precision therapy approaches for disorders of haploinsufficiency. In this Review, we discuss how miRNAs determine and control neuronal and glial functions, how this process is altered in states associated with hyperexcitability, and the prospects for miRNA targeting for the treatment of epilepsy.
Small non-coding RNAs known as microRNAs (miRNAs) are critical regulators of brain development and brain function.
Expression of miRNAs differs between cell types; in neurons, miRNA function responds to and shapes neuronal activity.
Epilepsy-inciting events, such as traumatic brain injury, cerebrovascular insults and status epilepticus, alter the expression and/or function of miRNAs, which could contribute to the pathogenesis of epilepsy.
In vivo targeting of miRNAs in animal models has identified several miRNAs that have functional roles in epilepsy.
Targeting of miRNAs is a potential strategy for the treatment and prevention of epilepsy, but challenges in the delivery and safety of therapeutics remain to be overcome.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Schmidt, D. & Sillanpaa, M. Evidence-based review on the natural history of the epilepsies. Curr. Opin. Neurol. 25, 159–163 (2012).
Beyenburg, S., Stavem, K. & Schmidt, D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 51, 7–26 (2010).
Raoof, R. et al. Cerebrospinal fluid microRNAs are potential biomarkers of temporal lobe epilepsy and status epilepticus. Sci. Rep. 7, 3328 (2017).
Henshall, D. C. Antagomirs and microRNA in status epilepticus. Epilepsia 54, 17–19 (2013).
Jolana, L. & Kamil, D. The role of microRNA in ischemic and hemorrhagic stroke. Curr. Drug Deliv. 14, 816–831 (2017).
Mirzaei, H. et al. MicroRNA: relevance to stroke diagnosis, prognosis, and therapy. J. Cell Physiol. 233, 856–865 (2018).
Vuokila, N. et al. miR-124-3p is a chronic regulator of gene expression after brain injury. Cell Mol. Life Sci. 75, 4557–4581 (2018).
Pan, Y. B., Sun, Z. L. & Feng, D. F. The role of microRNA in traumatic brain injury. Neuroscience 367, 189–199 (2017).
Kobayashi, M. et al. AGO CLIP reveals an activated network for acute regulation of brain glutamate homeostasis in ischemic stroke. Cell Rep. 28, 979–991.e6 (2019).
Brennan, G. P. et al. Dual and opposing roles of microRNA-124 in epilepsy are mediated through inflammatory and NRSF-dependent gene networks. Cell Rep. 14, 2402–2412 (2016).
Jimenez-Mateos, E. M. et al. miRNA expression profile after status epilepticus and hippocampal neuroprotection by targeting miR-132. Am. J. Pathol. 179, 2519–2532 (2011).
Schouten, M. et al. Multi-omics profile of the mouse dentate gyrus after kainic acid-induced status epilepticus. Sci. Data 3, 160068 (2016).
Jiang, L. et al. Inhibition of microRNA-103 attenuates inflammation and endoplasmic reticulum stress in atherosclerosis through disrupting the PTEN-mediated MAPK signaling. J. Cell Physiol. 235, 380–393 (2020).
Henry, R. J. et al. Inhibition of miR-155 limits neuroinflammation and improves functional recovery after experimental traumatic brain injury in mice. Neurotherapeutics 16, 216–230 (2019).
Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).
Kozomara, A., Birgaoanu, M. & Griffiths-Jones, S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 47, D155–D162 (2019).
Bartel, D. P. Metazoan microRNAs. Cell 173, 20–51 (2018). An outstanding review of miRNA function that includes details of the phenotypes of various miRNA knockout mice.
Nowakowski, T. J. et al. Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development. Nat. Neurosci. 21, 1784–1792 (2018). The first systematic analysis of miRNA in specific cell types in the human brain.
McCall, M. N. et al. Toward the human cellular microRNAome. Genome Res. 27, 1769–1781 (2017).
Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).
Konopka, W. et al. MicroRNA loss enhances learning and memory in mice. J. Neurosci. 30, 14835–14842 (2010).
Davis, T. H. et al. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J. Neurosci. 28, 4322–4330 (2008).
Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).
Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16, 720–728 (2002).
Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).
Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).
Hammond, S. M., Boettcher, S., Caudy, A. A., Kobayashi, R. & Hannon, G. J. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293, 1146–1150 (2001).
Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).
Chandradoss, S. D., Schirle, N. T., Szczepaniak, M., MacRae, I. J. & Joo, C. A dynamic search process underlies microRNA targeting. Cell 162, 96–107 (2015).
Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).
Chi, S. W., Zang, J. B., Mele, A. & Darnell, R. B. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009).
Moore, M. J. et al. miRNA-target chimeras reveal miRNA 3′-end pairing as a major determinant of Argonaute target specificity. Nat. Commun. 6, 8864 (2015).
Boudreau, R. L. et al. Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81, 294–305 (2014).
Didiano, D. & Hobert, O. Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat. Struct. Mol. Biol. 13, 849–851 (2006).
Vella, M. C., Choi, E. Y., Lin, S. Y., Reinert, K. & Slack, F. J. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3′UTR. Genes Dev. 18, 132–137 (2004).
Fabian, M. R., Sonenberg, N. & Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379 (2010).
Fabian, M. R. & Sonenberg, N. The mechanics of miRNA-mediated gene silencing: a look under the hood of miRISC. Nat. Struct. Mol. Biol. 19, 586–593 (2012).
Lytle, J. R., Yario, T. A. & Steitz, J. A. Target mRNAs are repressed as efficiently by microRNA-binding sites in the 5′ UTR as in the 3′ UTR. Proc. Natl Acad. Sci. USA 104, 9667–9672 (2007).
Orom, U. A., Nielsen, F. C. & Lund, A. H. MicroRNA-10a binds the 5′UTR of ribosomal protein mRNAs and enhances their translation. Mol. Cell 30, 460–471 (2008).
Tsai, N. P., Lin, Y. L. & Wei, L. N. MicroRNA mir-346 targets the 5′-untranslated region of receptor-interacting protein 140 (RIP140) mRNA and up-regulates its protein expression. Biochemical J. 424, 411–418 (2009).
Lee, I. et al. New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res. 19, 1175–1183 (2009).
Liu, C. et al. CLIP-based prediction of mammalian microRNA binding sites. Nucleic Acids Res. 41, e138 (2013).
Sambandan, S. et al. Activity-dependent spatially localized miRNA maturation in neuronal dendrites. Science 355, 634–637 (2017). This study shows how miRNA processing is linked to neuronal activity via NMDA-dependent entry of calcium at synapses.
Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).
Krichevsky, A. M., Sonntag, K. C., Isacson, O. & Kosik, K. S. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cell 24, 857–864 (2006).
Yoo, A. S., Staahl, B. T., Chen, L. & Crabtree, G. R. MicroRNA-mediated switching of chromatin-remodelling complexes in neural development. Nature 460, 642–646 (2009).
Coolen, M., Thieffry, D., Drivenes, O., Becker, T. S. & Bally-Cuif, L. miR-9 controls the timing of neurogenesis through the direct inhibition of antagonistic factors. Dev. Cell 22, 1052–1064 (2012).
Otaegi, G., Pollock, A., Hong, J. & Sun, T. MicroRNA miR-9 modifies motor neuron columns by a tuning regulation of FoxP1 levels in developing spinal cords. J. Neurosci. 31, 809–818 (2011).
Leucht, C. et al. MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary. Nat. Neurosci. 11, 641–648 (2008).
Bonev, B., Pisco, A. & Papalopulu, N. MicroRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis. Dev. Cell 20, 19–32 (2011).
Ghosh, T. et al. MicroRNAs establish robustness and adaptability of a critical gene network to regulate progenitor fate decisions during cortical neurogenesis. Cell Rep. 7, 1779–1788 (2014).
Sun, G. et al. miR-137 forms a regulatory loop with nuclear receptor TLX and LSD1 in neural stem cells. Nat. Commun. 2, 529 (2011).
Budde, H. et al. Control of oligodendroglial cell number by the miR-17-92 cluster. Development 137, 2127–2132 (2010).
Tan, C. L. et al. MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 342, 1254–1258 (2013). A landmark study demonstrating that genetic deletion of the brain-enriched miR-128 results in motor seizures and premature death in mice, and documenting the extensive dysregulation of gene networks in the brain following loss of miR-128.
Akerblom, M. et al. MicroRNA-124 is a subventricular zone neuronal fate determinant. J. Neurosci. 32, 8879–8889 (2012).
Hagemann-Jensen, M., Abdullayev, I., Sandberg, R. & Faridani, O. R. Small-seq for single-cell small-RNA sequencing. Nat. Protoc. 13, 2407–2424 (2018).
Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).
La Rocca, G. et al. In vivo, Argonaute-bound microRNAs exist predominantly in a reservoir of low molecular weight complexes not associated with mRNA. Proc. Natl Acad. Sci. USA 112, 767–772 (2015).
Leung, A. K. L. The whereabouts of microRNA actions: cytoplasm and beyond. Trends Cell Biol. 25, 601–610 (2015). An excellent review of the different locations within cells where miRNAs can act.
Rajgor, D., Sanderson, T. M., Amici, M., Collingridge, G. L. & Hanley, J. G. NMDAR-dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity. EMBO J. 37, e97943 (2018).
Liu, J., Valencia-Sanchez, M. A., Hannon, G. J. & Parker, R. MicroRNA-dependent localization of targeted mRNAs to mammalian P-bodies. Nat. Cell Biol. 7, 719–723 (2005).
Sen, G. L. & Blau, H. M. Argonaute 2/RISC resides in sites of mammalian mRNA decay known as cytoplasmic bodies. Nat. Cell Biol. 7, 633–636 (2005).
Leung, A. K., Calabrese, J. M. & Sharp, P. A. Quantitative analysis of Argonaute protein reveals microRNA-dependent localization to stress granules. Proc. Natl Acad. Sci. USA 103, 18125–18130 (2006).
Gibbings, D. J., Ciaudo, C., Erhardt, M. & Voinnet, O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11, 1143–1149 (2009).
Gagnon, K. T., Li, L., Chu, Y., Janowski, B. A. & Corey, D. R. RNAi factors are present and active in human cell nuclei. Cell Rep. 6, 211–221 (2014).
Risbud, R. M. & Porter, B. E. Changes in microRNA expression in the whole hippocampus and hippocampal synaptoneurosome fraction following pilocarpine induced status epilepticus. PLoS One 8, e53464 (2013).
Lugli, G., Larson, J., Martone, M. E., Jones, Y. & Smalheiser, N. R. Dicer and eIF2c are enriched at postsynaptic densities in adult mouse brain and are modified by neuronal activity in a calpain-dependent manner. J. Neurochem. 94, 896–905 (2005).
Cougot, N. et al. Dendrites of mammalian neurons contain specialized P-body-like structures that respond to neuronal activation. J. Neurosci. 28, 13793–13804 (2008).
Kan, A. A. et al. Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. Cell. Mol. Life Sci. 69, 3127–3145 (2012).
Antoniou, A., Baptista, M., Carney, N. & Hanley, J. G. PICK1 links Argonaute 2 to endosomes in neuronal dendrites and regulates miRNA activity. EMBO Rep. 15, 548–556 (2014).
Antoniou, A. et al. The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development. EMBO Rep. 19, e44853 (2018).
Jee, D. & Lai, E. C. Alteration of miRNA activity via context-specific modifications of Argonaute proteins. Trends Cell Biol. 24, 546–553 (2014).
Horman, S. R. et al. Akt-mediated phosphorylation of Argonaute 2 downregulates cleavage and upregulates translational repression of microRNA targets. Mol. Cell 50, 356–367 (2013).
Roberts, T. C. The microRNA biology of the mammalian nucleus. Mol. Ther. Nucleic Acids 3, e188 (2014).
Katz, S. et al. A nuclear role for miR-9 and Argonaute proteins in balancing quiescent and activated neural stem cell states. Cell Rep. 17, 1383–1398 (2016).
Khudayberdiev, S. A., Zampa, F., Rajman, M. & Schratt, G. A comprehensive characterization of the nuclear microRNA repertoire of post-mitotic neurons. Front. Mol. Neurosci. 6, 43 (2013).
Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).
Kim, D. H., Saetrom, P., Snove, O. Jr & Rossi, J. J. MicroRNA-directed transcriptional gene silencing in mammalian cells. Proc. Natl Acad. Sci. USA 105, 16230–16235 (2008).
Raoof, R. et al. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine 38, 127–141 (2018).
Denzler, R. et al. Impact of microRNA levels, target-site complementarity, and cooperativity on competing endogenous RNA-regulated gene expression. Mol. Cell 64, 565–579 (2016).
Men, Y. et al. Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS. Nat. Commun. 10, 4136 (2019).
Park, I. et al. Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines. Proc. Natl Acad. Sci. USA 116, 9616–9621 (2019). In this study, individual molecules of miR-134 are visualized at the base of dendritic spines, and how this localization is related to synapse maturation and structure is elucidated.
Hayata-Takano, A. et al. Pituitary adenylate cyclase-activating polypeptide modulates dendritic spine maturation and morphogenesis via microRNA-132 upregulation. J. Neurosci. 39, 4208–4220 (2019).
Weiss, K., Treiber, T., Meister, G. & Schratt, G. The nuclear matrix protein Matr3 regulates processing of the synaptic microRNA-138-5p. Neurobiol. Learn. Mem. 159, 36–45 (2019).
Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006).
Zampa, F., Bicker, S. & Schratt, G. Activity-dependent Pre-miR-134 dendritic localization is required for hippocampal neuron dendritogenesis. Front. Mol. Neurosci. 11, 171 (2018).
Bicker, S. et al. The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134. Genes Dev. 27, 991–996 (2013).
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007). This study provides the first evidence that miRNAs can be packaged into exosomes to mediate a form of paracrine, intercellular communication.
Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011).
Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980 (2013).
Xu, B. et al. Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res. 27, 882–897 (2017).
Simeoli, R. et al. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat. Commun. 8, 1778 (2017).
Morel, L. et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem. 288, 7105–7116 (2013).
Gitai, D. L. G. et al. Extracellular vesicles in the forebrain display reduced miR-346 and miR-331-3p in a rat model of chronic temporal lobe epilepsy. Mol. Neurobiol. 57, 1674-1687 (2020).
Batool, A. et al. Altered biogenesis and microRNA content of hippocampal exosomes following experimental status epilepticus. Front Neurosci. 13, 1404 (2020).
Yan, S. et al. Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget 8, 4136–4146 (2017).
Chevillet, J. R. et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl. Acad. Sci. USA 111, 14888–14893 (2014).
Sanuki, R. et al. miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat. Neurosci. 14, 1125–1134 (2011).
Shibata, M., Nakao, H., Kiyonari, H., Abe, T. & Aizawa, S. MicroRNA-9 regulates neurogenesis in mouse telencephalon by targeting multiple transcription factors. J. Neurosci. 31, 3407–3422 (2011).
Williams, A. H. et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549–1554 (2009).
Liu, N. et al. microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice. J. Clin. Invest. 122, 2054–2065 (2012).
Andolina, D. et al. Effects of lack of microRNA-34 on the neural circuitry underlying the stress response and anxiety. Neuropharmacology 107, 305–316 (2016).
Wang, H. et al. miR-219 cooperates with miR-338 in myelination and promotes myelin repair in the CNS. Dev. Cell 40, 566–582 (2017).
Banerjee, P. N., Filippi, D. & Allen Hauser, W. The descriptive epidemiology of epilepsy — a review. Epilepsy Res. 85, 31–45 (2009).
Pitkanen, A., Roivainen, R. & Lukasiuk, K. Development of epilepsy after ischaemic stroke. Lancet Neurol. 15, 185–197 (2016).
Fiest, K. M. et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 88, 296–303 (2017).
French, J. A. et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann. Neurol. 34, 774–780 (1993).
Loscher, W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 167, 107605 (2020).
Dudek, F. E. & Staley, K. J. in Jasper’s Basic Mechanisms of the Epilepsies (eds Noebels, J. L., Avoli, M., Rogawski, M. A., Olsen, R. W. & Delgado-Escueta, A. V.) 405–415 (NCBI, 2012).
Pitkanen, A. et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 15, 843–856 (2016).
Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).
Dingledine, R., Varvel, N. H. & Dudek, F. E. When and how do seizures kill neurons, and is cell death relevant to epileptogenesis? Adv. Exp. Med. Biol. 813, 109–122 (2014).
Kovac, S., Abramov, A. Y. & Walker, M. C. Energy depletion in seizures: anaplerosis as a strategy for future therapies. Neuropharmacology 69, 96–104 (2013).
Naegele, J. R. Neuroprotective strategies to avert seizure-induced neurodegeneration in epilepsy. Epilepsia 48, 107–117 (2007).
Henshall, D. C. & Simon, R. P. Epilepsy and apoptosis pathways. J. Cereb. Blood Flow Metab. 25, 1557–1572 (2005).
Swann, J. W. & Rho, J. M. How is homeostatic plasticity important in epilepsy? Adv. Exp. Med. Biol. 813, 123–131 (2014).
Bui, A., Kim, H. K., Maroso, M. & Soltesz, I. Microcircuits in epilepsy: heterogeneity and hub cells in network synchronization. Cold Spring Harb. Perspect. Med. 5, a022855 (2015).
Kokaia, M. Seizure-induced neurogenesis in the adult brain. Eur. J. Neurosci. 33, 1133–1138 (2011).
Bielefeld, P., van Vliet, E. A., Gorter, J. A., Lucassen, P. J. & Fitzsimons, C. P. Different subsets of newborn granule cells: a possible role in epileptogenesis? Eur. J. Neurosci. 39, 1–11 (2014).
Danzer, S. C. Contributions of adult-generated granule cells to hippocampal pathology in temporal lobe epilepsy: a neuronal bestiary. Brain Plast. 3, 169–181 (2018).
Robel, S. & Sontheimer, H. Glia as drivers of abnormal neuronal activity. Nat. Neurosci. 19, 28–33 (2016).
Lipponen, A. et al. Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury. Acta Neuropathol. Commun. 6, 17 (2018).
McClelland, S. et al. Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann. Neurol. 70, 454–464 (2011).
Hu, Y. et al. Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor. J. Biol. Chem. 283, 9328–9340 (2008).
McClelland, S. et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 3, e01267 (2014).
Miller-Delaney, S. F. et al. Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. Brain 138, 616–631 (2015).
Hauser, R. M., Henshall, D. C. & Lubin, F. D. The epigenetics of epilepsy and its progression. Neuroscientist 24, 186–200 (2018).
Kobow, K. et al. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 126, 741–756 (2013).
Kobow, K. et al. Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia. Epilepsia 60, 1091–1103 (2019).
Henshall, D. C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 15, 1368–1376 (2016).
Jimenez-Mateos, E. M. et al. Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat. Med. 18, 1087–1094 (2012). This study is the first in vivo demonstration that targeting an miRNA can reduce seizures.
Rajman, M. et al. A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses. EMBO J. 36, 1770–1787 (2017).
Bielefeld, P., Mooney, C., Henshall, D. C. & Fitzsimons, C. P. miRNA-mediated regulation of adult hippocampal neurogenesis; implications for epilepsy. Brain Plasticity 3, 43–59 (2017).
Rensing, N. et al. In vivo imaging of dendritic spines during electrographic seizures. Ann. Neurol. 58, 888–898 (2005).
Sone, D. et al. Abnormal neurite density and orientation dispersion in unilateral temporal lobe epilepsy detected by advanced diffusion imaging. NeuroImage. Clin. 20, 772–782 (2018).
Singh, S. P., He, X., McNamara, J. O. & Danzer, S. C. Morphological changes among hippocampal dentate granule cells exposed to early kindling-epileptogenesis. Hippocampus 23, 1309–1320 (2013).
Karlocai, M. R. et al. Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. Brain Struct. Funct. 221, 3601–3615 (2016).
Surges, R. et al. Hyperpolarization-activated cation current Ih of dentate gyrus granule cells is upregulated in human and rat temporal lobe epilepsy. Biochem. Biophys. Res. Commun. 420, 156–160 (2012).
Tiwari, D. et al. MicroRNA inhibition upregulates hippocampal A-type potassium current and reduces seizure frequency in a mouse model of epilepsy. Neurobiol. Dis. 130, 104508 (2019).
Engel, T. et al. A calcium-sensitive feed-forward loop regulating the expression of the ATP-gated purinergic P2X7 receptor via specificity protein 1 and microRNA-22. Biochim. Biophys. Acta Mol. Cell Res. 1864, 255–266 (2017).
Jimenez-Pacheco, A. et al. Transient P2X7 receptor antagonism produces lasting reductions in spontaneous seizures and gliosis in experimental temporal lobe epilepsy. J. Neurosci. 36, 5920–5932 (2016).
Sakai, A. et al. MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain. Nat. Commun. 8, 16079 (2017).
Chen, X. & Rosbash, M. MicroRNA-92a is a circadian modulator of neuronal excitability in Drosophila. Nat. Commun. 8, 14707 (2017).
Letellier, M. et al. miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling. Nat. Neurosci. 17, 1040–1042 (2014).
McKiernan, R. C. et al. Reduced mature microRNA levels in association with Dicer loss in human temporal lobe epilepsy with hippocampal sclerosis. PLoS One 7, e35921 (2012).
Lippi, G. et al. MicroRNA-101 regulates multiple developmental programs to constrain excitation in adult neural networks. Neuron 92, 1337–1351 (2016).
Lozovaya, N. et al. GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease. Nat. Commun. 9, 1422 (2018).
Hansen, K. F. et al. miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct. Funct. 218, 817–831 (2013).
Hansen, K. F. et al. Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome. Learn. Mem. 23, 61–71 (2016).
Mazziotti, R. et al. Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception. Nat. Commun. 8, 15488 (2017).
Nudelman, A. S. et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus 20, 492–498 (2010).
Magill, S. T. et al. microRNA-132 regulates dendritic growth and arborization of newborn neurons in the adult hippocampus. Proc. Natl Acad. Sci. USA 107, 20382–20387 (2010).
Vo, N. et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl Acad. Sci. USA 102, 16426–16431 (2005).
Hancock, M. L., Preitner, N., Quan, J. & Flanagan, J. G. MicroRNA-132 is enriched in developing axons, locally regulates Rasa1 mRNA, and promotes axon extension. J. Neurosci. 34, 66–78 (2014).
Soreq, H. & Wolf, Y. NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol. Med. 17, 548–555 (2011).
Hwang, J. Y., Kaneko, N., Noh, K. M., Pontarelli, F. & Zukin, R. S. The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J. Mol. Biol. 426, 3454–3466 (2014).
Fiore, R. et al. MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression. EMBO J. 33, 2231–2246 (2014).
Jimenez-Mateos, E. M. et al. Antagomirs targeting microRNA-134 increase hippocampal pyramidal neuron spine volume in vivo and protect against pilocarpine-induced status epilepticus. Brain Struct. Funct. 220, 2387–2399 (2015).
Reschke, C. R. et al. Potent anti-seizure effects of locked nucleic acid antagomirs targeting miR-134 in multiple mouse and rat models of epilepsy. Mol. Ther. Nucleic Acids 6, 45–56 (2017).
Hu, Z. et al. miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression. Nat. Commun. 5, 3263 (2014).
Vangoor, V. R. et al. Antagonizing increased miR-135a levels at the chronic stage of experimental TLE reduces spontaneous recurrent seizures. J. Neurosci. 39, 5064–5079 (2019).
Bekenstein, U. et al. Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity. Proc. Natl Acad. Sci. USA 114, E4996–E5005 (2017).
Gross, C. et al. MicroRNA-mediated downregulation of the potassium channel Kv4.2 contributes to seizure onset. Cell Rep. 17, 37–45 (2016).
Boison, D. & Steinhauser, C. Epilepsy and astrocyte energy metabolism. Glia 66, 1235–1243 (2018).
Patel, D. C., Tewari, B. P., Chaunsali, L. & Sontheimer, H. Neuron-glia interactions in the pathophysiology of epilepsy. Nat. Rev. Neurosci. 20, 282–297 (2019).
Blumcke, I. et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N. Engl. J. Med. 377, 1648–1656 (2017).
Karve, I. P., Taylor, J. M. & Crack, P. J. The contribution of astrocytes and microglia to traumatic brain injury. Br. J. Pharmacol. 173, 692–702 (2016).
Choudhury, G. R. & Ding, S. Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol. Dis. 85, 234–244 (2016).
Ortinski, P. I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).
Robel, S. et al. Reactive astrogliosis causes the development of spontaneous seizures. J. Neurosci. 35, 3330–3345 (2015).
Eid, T. et al. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363, 28–37 (2004).
Shen, H. Y. et al. Overexpression of adenosine kinase in cortical astrocytes and focal neocortical epilepsy in mice. J. Neurosurg. 120, 628–638 (2014).
Aronica, E. et al. Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia 52, 1645–1655 (2011).
Masino, S. A. et al. A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors. J. Clin. Invest. 121, 2679–2683 (2011).
Kiese, K., Jablonski, J., Boison, D. & Kobow, K. Dynamic regulation of the adenosine kinase gene during early postnatal brain development and maturation. Front. Mol. Neurosci. 9, 99 (2016).
Boison, D. Adenosinergic signaling in epilepsy. Neuropharmacology 104, 131–139 (2016).
Maroso, M. et al. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8, 304–315 (2011).
Maroso, M. et al. Interleukin-1 type 1 receptor/Toll-like receptor signalling in epilepsy: the importance of IL-1beta and high-mobility group box 1. J. Intern. Med. 270, 319–326 (2011).
Missault, S. et al. Neuroimaging of subacute brain inflammation and microstructural changes predicts long-term functional outcome after experimental traumatic brain injury. J. Neurotrauma 36, 768–788 (2019).
Patterson, K. P. et al. Rapid, coordinate inflammatory responses after experimental febrile status epilepticus: implications for epileptogenesis. eNeuro https://doi.org/10.1523/eneuro.0034-15.2015 (2015).
Dube, C., Vezzani, A., Behrens, M., Bartfai, T. & Baram, T. Z. Interleukin-1beta contributes to the generation of experimental febrile seizures. Ann. Neurol. 57, 152–155 (2005).
Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).
Buller, B. et al. MicroRNA-21 protects neurons from ischemic death. FEBS J. 277, 4299–4307 (2010).
Redell, J. B., Zhao, J. & Dash, P. K. Altered expression of miRNA-21 and its targets in the hippocampus after traumatic brain injury. J. Neurosci. Res. 89, 212–221 (2011).
Meissner, L. et al. Temporal profile of microRNA expression in contused cortex after traumatic brain injury in mice. J. Neurotrauma 33, 713–720 (2016).
Bot, A. M., Debski, K. J. & Lukasiuk, K. Alterations in miRNA levels in the dentate gyrus in epileptic rats. PLoS One 8, e76051 (2013).
Harrison, E. B. et al. Traumatic brain injury increases levels of miR-21 in extracellular vesicles: implications for neuroinflammation. FEBS Open Bio 6, 835–846 (2016).
Bhalala, O. G. et al. microRNA-21 regulates astrocytic response following spinal cord injury. J. Neurosci. 32, 17935–17947 (2012).
Jovicic, A. et al. Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J. Neurosci. 33, 5127–5137 (2013). An in vitro study in which various miRNAs that are specific to brain cell types are identified in cultured cells.
Meares, G. P. et al. MicroRNA-31 is required for astrocyte specification. Glia 66, 987–998 (2018).
Foo, L. C., Song, S. & Cohen, S. M. miR-31 mutants reveal continuous glial homeostasis in the adult Drosophila brain. EMBO J. 36, 1215–1226 (2017).
Avansini, S. H. et al. Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia. Ann. Neurol. 83, 623–635 (2018).
Gorter, J. A. et al. Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol. Dis. 62, 508–520 (2014).
Kretschmann, A. et al. Different microRNA profiles in chronic epilepsy versus acute seizure mouse models. J. Mol. Neurosci. 55, 466–479 (2015).
McKiernan, R. C. et al. Expression profiling the microRNA response to epileptic preconditioning identifies miR-184 as a modulator of seizure-induced neuronal death. Exp. Neurol. 237, 346–354 (2012).
Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).
Allen, N. J. & Lyons, D. A. Glia as architects of central nervous system formation and function. Science 362, 181–185 (2018).
Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).
Maroso, M. et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat. Med. 16, 413–419 (2010).
Choy, M. et al. A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J. Neurosci. 34, 8672–8684 (2014).
Ali, I., Chugh, D. & Ekdahl, C. T. Role of fractalkine-CX3CR1 pathway in seizure-induced microglial activation, neurodegeneration, and neuroblast production in the adult rat brain. Neurobiol. Dis. 74, 194–203 (2015).
Prada, I. et al. Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations. Acta Neuropathol. 135, 529–550 (2018).
Aronica, E. et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur. J. Neurosci. 31, 1100–1107 (2010). The first report of altered expression of an miRNA in human epilepsy.
Roncon, P. et al. MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy-comparison with human epileptic samples. Sci. Rep. 5, 14143 (2015).
Iori, V. et al. Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol. Dis. 99, 12–23 (2017).
Schouten, M. et al. MicroRNA-124 and -137 cooperativity controls caspase-3 activity through BCL2L13 in hippocampal neural stem cells. Sci. Rep. 5, 12448 (2015).
Cai, Z. et al. Antagonist targeting microRNA-155 protects against lithium-pilocarpine-induced status epilepticus in C57BL/6 mice by activating brain-derived neurotrophic factor. Front. Pharmacol. 7, 129 (2016).
Pena-Philippides, J. C., Caballero-Garrido, E., Lordkipanidze, T. & Roitbak, T. In vivo inhibition of miR-155 significantly alters post-stroke inflammatory response. J. Neuroinflammation 13, 287 (2016).
Cardoso, A. L., Guedes, J. R., Pereira de Almeida, L. & Pedroso de Lima, M. C. miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production. Immunology 135, 73–88 (2012).
McCoy, C. E. miR-155 dysregulation and therapeutic intervention in multiple sclerosis. Adv. Exp. Med. Biol. 1024, 111–131 (2017).
Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).
Guedes, J. R. et al. Early miR-155 upregulation contributes to neuroinflammation in Alzheimer’s disease triple transgenic mouse model. Hum. Mol. Genet. 23, 6286–6301 (2014).
Caballero-Garrido, E. et al. In vivo inhibition of miR-155 promotes recovery after experimental mouse stroke. J. Neurosci. 35, 12446–12464 (2015).
Bruen, R., Fitzsimons, S. & Belton, O. miR-155 in the resolution of atherosclerosis. Front. Pharmacol. 10, 463 (2019).
Huang, L. G., Zou, J. & Lu, Q. C. Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis by activating Sestrin-3. Brain Res. 1689, 109–122 (2018).
Fu, H. et al. Silencing microRNA-155 attenuates kainic acid-induced seizure by inhibiting microglia activation. Neuroimmunomodulation 26, 67–76 (2019).
Veremeyko, T. et al. Neuronal extracellular microRNAs miR-124 and miR-9 mediate cell-cell communication between neurons and microglia. J. Neurosci. Res. 97, 162–184 (2019).
Shlosberg, D., Benifla, M., Kaufer, D. & Friedman, A. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat. Rev. Neurol. 6, 393–403 (2010).
Broekaart, D. W. M. et al. Activation of the innate immune system is evident throughout epileptogenesis and is associated with blood-brain barrier dysfunction and seizure progression. Epilepsia 59, 1931–1944 (2018).
Jiang, X. et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol. 163-164, 144–171 (2018).
Ruber, T. et al. Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy. Brain 141, 2952–2965 (2018).
Liu da, Z. et al. Elevating microRNA-122 in blood improves outcomes after temporary middle cerebral artery occlusion in rats. J. Cereb. Blood Flow. Metab. 36, 1374–1383 (2016).
Wan, Y. et al. MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes. FASEB J. 32, 3133–3148 (2018).
Cheng, Y. D., Al-Khoury, L. & Zivin, J. A. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 1, 36–45 (2004).
Gladstone, D. J., Black, S. E. & Hakim, A. M. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke 33, 2123–2136 (2002).
Janssen, H. L. et al. Treatment of HCV infection by targeting microRNA. N. Engl. J. Med. 368, 1685–1694 (2013). Important results of a clinical trial to determine the safety and efficacy of an miRNA inhibitor in a human disease.
Franzoni, E. et al. miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6. eLife 4, e04263 (2015).
Lee, S. T. et al. Inhibition of miR-203 reduces spontaneous recurrent seizures in mice. Mol. Neurobiol. 54, 3300–3308 (2017).
Gao, X. et al. Silencing microRNA-134 alleviates hippocampal damage and occurrence of spontaneous seizures after intraventricular kainic acid-induced status epilepticus in rats. Front. Cell. Neurosci. 13, 145 (2019).
Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
Walker, M. C. & Kullmann, D. M. Optogenetic and chemogenetic therapies for epilepsy. Neuropharmacology 168, 107751 (2020).
Hinderer, C. et al. Severe toxicity in nonhuman primates and piglets following high-dose intravenous administration of an adeno-associated virus vector expressing human SMN. Hum. Gene Ther. 29, 285–298 (2018).
Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).
Braasch, D. A. & Corey, D. R. Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA. Chem. Biol. 8, 1–7 (2001).
Tolstrup, N. et al. OligoDesign: optimal design of LNA (locked nucleic acid) oligonucleotide capture probes for gene expression profiling. Nucleic Acids Res. 31, 3758–3762 (2003).
Kumar, R. et al. The first analogues of LNA (locked nucleic acids): phosphorothioate-LNA and 2′-thio-LNA. Bioorg. Med. Chem. Lett. 8, 2219–2222 (1998).
Bianchini, D. et al. First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide to exon 4 of the androgen receptor mRNA in patients with castration-resistant prostate cancer. Br. J. Cancer 109, 2579–2586 (2013).
Wood, M. J. A., Talbot, K. & Bowerman, M. Spinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape. Hum. Mol. Genet. 26, R151–R159 (2017).
Kim, J. et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 381, 1644–1652 (2019).
Straarup, E. M. et al. Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates. Nucleic Acids Res. 38, 7100–7111 (2010).
Mollaei, H., Safaralizadeh, R. & Rostami, Z. MicroRNA replacement therapy in cancer. J. Cell. Physiol. 234, 12369–12384 (2019).
van Gestel, M. A. et al. shRNA-induced saturation of the microRNA pathway in the rat brain. Gene Ther. 21, 205–211 (2014).
Jimenez-Mateos, E. M. et al. microRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. Sci. Rep. 5, 17486 (2015).
Zhan, L. et al. Protective role of miR-23b-3p in kainic acid-induced seizure. Neuroreport 27, 764–768 (2016).
Sano, T. et al. MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death Dis. 3, e287 (2012).
Hu, K. et al. MicroRNA expression profile of the hippocampus in a rat model of temporal lobe epilepsy and miR-34a-targeted neuroprotection against hippocampal neurone cell apoptosis post-status epilepticus. BMC Neurosci. 13, 115 (2012).
Gan, J. et al. miR-96 attenuates status epilepticus-induced brain injury by directly targeting Atg7 and Atg16L1. Sci. Rep. 7, 10270 (2017).
Ren, L., Zhu, R. & Li, X. Silencing miR-181a produces neuroprotection against hippocampus neuron cell apoptosis post-status epilepticus in a rat model and in children with temporal lobe epilepsy. Genet. Mol. Res. 15, gmr.15017798 (2016).
Wang, D. et al. Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade. Epilepsia 57, 706–716 (2016).
Xiang, L., Ren, Y., Li, X., Zhao, W. & Song, Y. MicroRNA-204 suppresses epileptiform discharges through regulating TrkB-ERK1/2-CREB signaling in cultured hippocampal neurons. Brain Res. 1639, 99–107 (2016).
Chen, L., Zheng, H. & Zhang, S. Involvement of upregulation of miR-210 in a rat epilepsy model. Neuropsychiatr. Dis. Treat. 12, 1731–1737 (2016).
Zheng, H. et al. MiR-219 protects against seizure in the kainic acid model of epilepsy. Mol. Neurobiol. 53, 1–7 (2016).
The authors thank the following funding agencies for support: Science Foundation Ireland (SFI) under grant number 16/RC/3948, co-funded under the European Regional Development Fund and by FutureNeuro industry partners; SFI awards 13/IA/1891, 11/TIDA/B1988, 18/SIRG/5646; the Health Research Board Ireland (HRA-POR-2013–325); the Irish Research Council; the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement number 602130; and H2020 Marie S Curie Individual Fellowship (EpimiRGen). The authors also thank their many colleagues.
D.C.H. is an inventor on US patent no. US 9,803,200 B2, “Inhibition of microRNA-134 for the treatment of seizure-related disorders and neurologic injuries”. G.P.B. declares no competing interests.
Peer review information
Nature Reviews Neurology thanks H. Lerche, W. Lukiw and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Processing bodies
Ribonucleoprotein aggregates found in the cytoplasm that are composed of translationally repressed mRNAs and proteins that are involved in mRNA decay.
- Synaptic scaling
A form of compensatory neuroplasticity in which neurons respond to persistently high activity by reducing synaptic strength to restore activity to within the normal dynamic range.
- miRNA sponge
A nucleotide construct made up of repeats of sequences that are complementary to microRNA and that consequently binds and/or absorbs any available microRNA.
About this article
Cite this article
Brennan, G.P., Henshall, D.C. MicroRNAs as regulators of brain function and targets for treatment of epilepsy. Nat Rev Neurol 16, 506–519 (2020). https://doi.org/10.1038/s41582-020-0369-8
The Egyptian Journal of Neurology, Psychiatry and Neurosurgery (2021)
Nature Reviews Neurology (2021)
Molecular Neurobiology (2021)