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  • Review Article
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MicroRNAs as regulators of brain function and targets for treatment of epilepsy

Nature Reviews Neurology volume 16, pages 506–519 (2020)Cite this article

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Abstract

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.

Key points

  • 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.

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Fig. 1: MicroRNA nomenclature.
Fig. 2: Epilepsy-related signalling pathways that are regulated by microRNAs in neurons and glia.
Fig. 3: Activity-dependent localized microRNA maturation in neurons.

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References

  1. Schmidt, D. & Sillanpaa, M. Evidence-based review on the natural history of the epilepsies. Curr. Opin. Neurol. 25, 159–163 (2012).

    PubMed  Google Scholar 

  2. 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).

    CAS  PubMed  Google Scholar 

  3. Raoof, R. et al. Cerebrospinal fluid microRNAs are potential biomarkers of temporal lobe epilepsy and status epilepticus. Sci. Rep. 7, 3328 (2017).

    PubMed  PubMed Central  Google Scholar 

  4. Henshall, D. C. Antagomirs and microRNA in status epilepticus. Epilepsia 54, 17–19 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jolana, L. & Kamil, D. The role of microRNA in ischemic and hemorrhagic stroke. Curr. Drug Deliv. 14, 816–831 (2017).

    CAS  PubMed  Google Scholar 

  6. Mirzaei, H. et al. MicroRNA: relevance to stroke diagnosis, prognosis, and therapy. J. Cell Physiol. 233, 856–865 (2018).

    CAS  PubMed  Google Scholar 

  7. 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).

    CAS  PubMed  Google Scholar 

  8. Pan, Y. B., Sun, Z. L. & Feng, D. F. The role of microRNA in traumatic brain injury. Neuroscience 367, 189–199 (2017).

    CAS  PubMed  Google Scholar 

  9. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schouten, M. et al. Multi-omics profile of the mouse dentate gyrus after kainic acid-induced status epilepticus. Sci. Data 3, 160068 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. 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).

    CAS  PubMed  Google Scholar 

  16. Kozomara, A., Birgaoanu, M. & Griffiths-Jones, S. miRBase: from microRNA sequences to function. Nucleic Acids Res. 47, D155–D162 (2019).

    CAS  PubMed  Google Scholar 

  17. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. McCall, M. N. et al. Toward the human cellular microRNAome. Genome Res. 27, 1769–1781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).

    CAS  PubMed  Google Scholar 

  21. Konopka, W. et al. MicroRNA loss enhances learning and memory in mice. J. Neurosci. 30, 14835–14842 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. Identification of novel genes coding for small expressed RNAs. Science 294, 853–858 (2001).

    CAS  PubMed  Google Scholar 

  24. Mourelatos, Z. et al. miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. Genes Dev. 16, 720–728 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee, Y. et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 23, 4051–4060 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  27. 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).

    CAS  PubMed  Google Scholar 

  28. Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Selbach, M. et al. Widespread changes in protein synthesis induced by microRNAs. Nature 455, 58–63 (2008).

    CAS  PubMed  Google Scholar 

  31. Chi, S. W., Zang, J. B., Mele, A. & Darnell, R. B. Argonaute HITS-CLIP decodes microRNA-mRNA interaction maps. Nature 460, 479–486 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  PubMed  Google Scholar 

  33. Boudreau, R. L. et al. Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron 81, 294–305 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Fabian, M. R., Sonenberg, N. & Filipowicz, W. Regulation of mRNA translation and stability by microRNAs. Annu. Rev. Biochem. 79, 351–379 (2010).

    CAS  PubMed  Google Scholar 

  37. 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).

    CAS  PubMed  Google Scholar 

  38. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    PubMed  Google Scholar 

  40. 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).

    CAS  Google Scholar 

  41. Lee, I. et al. New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites. Genome Res. 19, 1175–1183 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu, C. et al. CLIP-based prediction of mammalian microRNA binding sites. Nucleic Acids Res. 41, e138 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 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.

    CAS  PubMed  Google Scholar 

  44. Lim, L. P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005).

    CAS  PubMed  Google Scholar 

  45. 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).

    CAS  Google Scholar 

  46. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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).

    CAS  PubMed  Google Scholar 

  48. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Leucht, C. et al. MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary. Nat. Neurosci. 11, 641–648 (2008).

    CAS  PubMed  Google Scholar 

  50. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  PubMed  Google Scholar 

  52. 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).

    PubMed  Google Scholar 

  53. Budde, H. et al. Control of oligodendroglial cell number by the miR-17-92 cluster. Development 137, 2127–2132 (2010).

    CAS  PubMed  Google Scholar 

  54. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Akerblom, M. et al. MicroRNA-124 is a subventricular zone neuronal fate determinant. J. Neurosci. 32, 8879–8889 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. Hagemann-Jensen, M., Abdullayev, I., Sandberg, R. & Faridani, O. R. Small-seq for single-cell small-RNA sequencing. Nat. Protoc. 13, 2407–2424 (2018).

    CAS  PubMed  Google Scholar 

  57. Alarcon, C. R., Lee, H., Goodarzi, H., Halberg, N. & Tavazoie, S. F. N6-methyladenosine marks primary microRNAs for processing. Nature 519, 482–485 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 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).

    PubMed  PubMed Central  Google Scholar 

  59. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  PubMed  Google Scholar 

  63. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 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).

    CAS  PubMed  Google Scholar 

  65. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 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).

    CAS  PubMed  Google Scholar 

  68. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Antoniou, A. et al. The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development. EMBO Rep. 19, e44853 (2018).

    PubMed  Google Scholar 

  72. Jee, D. & Lai, E. C. Alteration of miRNA activity via context-specific modifications of Argonaute proteins. Trends Cell Biol. 24, 546–553 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Roberts, T. C. The microRNA biology of the mammalian nucleus. Mol. Ther. Nucleic Acids 3, e188 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    PubMed  PubMed Central  Google Scholar 

  77. Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004).

    CAS  PubMed  Google Scholar 

  78. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Raoof, R. et al. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine 38, 127–141 (2018).

    PubMed  PubMed Central  Google Scholar 

  80. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 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).

    PubMed  PubMed Central  Google Scholar 

  82. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 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).

    PubMed  PubMed Central  Google Scholar 

  84. 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).

    CAS  PubMed  Google Scholar 

  85. Schratt, G. M. et al. A brain-specific microRNA regulates dendritic spine development. Nature 439, 283–289 (2006).

    CAS  PubMed  Google Scholar 

  86. 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).

    PubMed  PubMed Central  Google Scholar 

  87. Bicker, S. et al. The DEAH-box helicase DHX36 mediates dendritic localization of the neuronal precursor-microRNA-134. Genes Dev. 27, 991–996 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 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.

    CAS  PubMed  Google Scholar 

  89. Mittelbrunn, M. et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2, 282 (2011).

    PubMed  Google Scholar 

  90. Villarroya-Beltri, C. et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980 (2013).

    PubMed  Google Scholar 

  91. Xu, B. et al. Neurons secrete miR-132-containing exosomes to regulate brain vascular integrity. Cell Res. 27, 882–897 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Simeoli, R. et al. Exosomal cargo including microRNA regulates sensory neuron to macrophage communication after nerve trauma. Nat. Commun. 8, 1778 (2017).

    PubMed  PubMed Central  Google Scholar 

  93. Morel, L. et al. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem. 288, 7105–7116 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 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).

    CAS  PubMed  Google Scholar 

  95. Batool, A. et al. Altered biogenesis and microRNA content of hippocampal exosomes following experimental status epilepticus. Front Neurosci. 13, 1404 (2020).

  96. Yan, S. et al. Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget 8, 4136–4146 (2017).

    PubMed  Google Scholar 

  97. Chevillet, J. R. et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl. Acad. Sci. USA 111, 14888–14893 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Sanuki, R. et al. miR-124a is required for hippocampal axogenesis and retinal cone survival through Lhx2 suppression. Nat. Neurosci. 14, 1125–1134 (2011).

    CAS  PubMed  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Williams, A. H. et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549–1554 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Banerjee, P. N., Filippi, D. & Allen Hauser, W. The descriptive epidemiology of epilepsy — a review. Epilepsy Res. 85, 31–45 (2009).

    PubMed  PubMed Central  Google Scholar 

  105. Pitkanen, A., Roivainen, R. & Lukasiuk, K. Development of epilepsy after ischaemic stroke. Lancet Neurol. 15, 185–197 (2016).

    PubMed  Google Scholar 

  106. Fiest, K. M. et al. Prevalence and incidence of epilepsy: a systematic review and meta-analysis of international studies. Neurology 88, 296–303 (2017).

    PubMed  PubMed Central  Google Scholar 

  107. French, J. A. et al. Characteristics of medial temporal lobe epilepsy: I. Results of history and physical examination. Ann. Neurol. 34, 774–780 (1993).

    CAS  PubMed  Google Scholar 

  108. Loscher, W. The holy grail of epilepsy prevention: preclinical approaches to antiepileptogenic treatments. Neuropharmacology 167, 107605 (2020).

    PubMed  Google Scholar 

  109. 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).

  110. Pitkanen, A. et al. Advances in the development of biomarkers for epilepsy. Lancet Neurol. 15, 843–856 (2016).

    CAS  PubMed  Google Scholar 

  111. Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).

    CAS  PubMed  Google Scholar 

  112. 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).

    PubMed  PubMed Central  Google Scholar 

  113. Kovac, S., Abramov, A. Y. & Walker, M. C. Energy depletion in seizures: anaplerosis as a strategy for future therapies. Neuropharmacology 69, 96–104 (2013).

    CAS  PubMed  Google Scholar 

  114. Naegele, J. R. Neuroprotective strategies to avert seizure-induced neurodegeneration in epilepsy. Epilepsia 48, 107–117 (2007).

    CAS  PubMed  Google Scholar 

  115. Henshall, D. C. & Simon, R. P. Epilepsy and apoptosis pathways. J. Cereb. Blood Flow Metab. 25, 1557–1572 (2005).

    CAS  PubMed  Google Scholar 

  116. Swann, J. W. & Rho, J. M. How is homeostatic plasticity important in epilepsy? Adv. Exp. Med. Biol. 813, 123–131 (2014).

    PubMed  Google Scholar 

  117. 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).

    PubMed  PubMed Central  Google Scholar 

  118. Kokaia, M. Seizure-induced neurogenesis in the adult brain. Eur. J. Neurosci. 33, 1133–1138 (2011).

    PubMed  Google Scholar 

  119. 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).

    PubMed  Google Scholar 

  120. 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).

    PubMed  PubMed Central  Google Scholar 

  121. Robel, S. & Sontheimer, H. Glia as drivers of abnormal neuronal activity. Nat. Neurosci. 19, 28–33 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 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).

    PubMed  PubMed Central  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. McClelland, S. et al. The transcription factor NRSF contributes to epileptogenesis by selective repression of a subset of target genes. eLife 3, e01267 (2014).

    PubMed  PubMed Central  Google Scholar 

  126. 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).

    PubMed  Google Scholar 

  127. Hauser, R. M., Henshall, D. C. & Lubin, F. D. The epigenetics of epilepsy and its progression. Neuroscientist 24, 186–200 (2018).

    CAS  PubMed  Google Scholar 

  128. Kobow, K. et al. Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol. 126, 741–756 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Kobow, K. et al. Genomic DNA methylation distinguishes subtypes of human focal cortical dysplasia. Epilepsia 60, 1091–1103 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Henshall, D. C. et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol. 15, 1368–1376 (2016).

    CAS  PubMed  Google Scholar 

  131. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Rajman, M. et al. A microRNA-129-5p/Rbfox crosstalk coordinates homeostatic downscaling of excitatory synapses. EMBO J. 36, 1770–1787 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 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).

    PubMed  PubMed Central  Google Scholar 

  134. Rensing, N. et al. In vivo imaging of dendritic spines during electrographic seizures. Ann. Neurol. 58, 888–898 (2005).

    PubMed  Google Scholar 

  135. 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).

    PubMed  PubMed Central  Google Scholar 

  136. 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).

    PubMed  Google Scholar 

  137. Karlocai, M. R. et al. Enhanced expression of potassium-chloride cotransporter KCC2 in human temporal lobe epilepsy. Brain Struct. Funct. 221, 3601–3615 (2016).

    CAS  PubMed  Google Scholar 

  138. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 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).

    CAS  PubMed  Google Scholar 

  141. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 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).

    PubMed  PubMed Central  Google Scholar 

  143. Chen, X. & Rosbash, M. MicroRNA-92a is a circadian modulator of neuronal excitability in Drosophila. Nat. Commun. 8, 14707 (2017).

    PubMed  PubMed Central  Google Scholar 

  144. Letellier, M. et al. miR-92a regulates expression of synaptic GluA1-containing AMPA receptors during homeostatic scaling. Nat. Neurosci. 17, 1040–1042 (2014).

    CAS  PubMed  Google Scholar 

  145. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Lippi, G. et al. MicroRNA-101 regulates multiple developmental programs to constrain excitation in adult neural networks. Neuron 92, 1337–1351 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Lozovaya, N. et al. GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease. Nat. Commun. 9, 1422 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Hansen, K. F. et al. miRNA-132: a dynamic regulator of cognitive capacity. Brain Struct. Funct. 218, 817–831 (2013).

    PubMed  Google Scholar 

  149. Hansen, K. F. et al. Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome. Learn. Mem. 23, 61–71 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Nudelman, A. S. et al. Neuronal activity rapidly induces transcription of the CREB-regulated microRNA-132, in vivo. Hippocampus 20, 492–498 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Vo, N. et al. A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis. Proc. Natl Acad. Sci. USA 102, 16426–16431 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Soreq, H. & Wolf, Y. NeurimmiRs: microRNAs in the neuroimmune interface. Trends Mol. Med. 17, 548–555 (2011).

    CAS  PubMed  Google Scholar 

  156. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Fiore, R. et al. MiR-134-dependent regulation of Pumilio-2 is necessary for homeostatic synaptic depression. EMBO J. 33, 2231–2246 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 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).

    CAS  PubMed  Google Scholar 

  159. 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).

    CAS  PubMed  Google Scholar 

  160. 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).

    PubMed  Google Scholar 

  161. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Gross, C. et al. MicroRNA-mediated downregulation of the potassium channel Kv4.2 contributes to seizure onset. Cell Rep. 17, 37–45 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Boison, D. & Steinhauser, C. Epilepsy and astrocyte energy metabolism. Glia 66, 1235–1243 (2018).

    PubMed  Google Scholar 

  165. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Blumcke, I. et al. Histopathological findings in brain tissue obtained during epilepsy surgery. N. Engl. J. Med. 377, 1648–1656 (2017).

    PubMed  Google Scholar 

  167. 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).

    CAS  PubMed  Google Scholar 

  168. Choudhury, G. R. & Ding, S. Reactive astrocytes and therapeutic potential in focal ischemic stroke. Neurobiol. Dis. 85, 234–244 (2016).

    PubMed  Google Scholar 

  169. Ortinski, P. I. et al. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci. 13, 584–591 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Robel, S. et al. Reactive astrogliosis causes the development of spontaneous seizures. J. Neurosci. 35, 3330–3345 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. 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).

    CAS  PubMed  Google Scholar 

  172. Shen, H. Y. et al. Overexpression of adenosine kinase in cortical astrocytes and focal neocortical epilepsy in mice. J. Neurosurg. 120, 628–638 (2014).

    CAS  PubMed  Google Scholar 

  173. Aronica, E. et al. Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy. Epilepsia 52, 1645–1655 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Masino, S. A. et al. A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors. J. Clin. Invest. 121, 2679–2683 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 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).

    PubMed  PubMed Central  Google Scholar 

  176. Boison, D. Adenosinergic signaling in epilepsy. Neuropharmacology 104, 131–139 (2016).

    CAS  PubMed  Google Scholar 

  177. Maroso, M. et al. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 8, 304–315 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 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).

    CAS  PubMed  Google Scholar 

  179. 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).

    PubMed  Google Scholar 

  180. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  181. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Butovsky, O. et al. Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

    CAS  PubMed  Google Scholar 

  183. Buller, B. et al. MicroRNA-21 protects neurons from ischemic death. FEBS J. 277, 4299–4307 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 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).

    CAS  PubMed  Google Scholar 

  185. Meissner, L. et al. Temporal profile of microRNA expression in contused cortex after traumatic brain injury in mice. J. Neurotrauma 33, 713–720 (2016).

    PubMed  Google Scholar 

  186. Bot, A. M., Debski, K. J. & Lukasiuk, K. Alterations in miRNA levels in the dentate gyrus in epileptic rats. PLoS One 8, e76051 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Bhalala, O. G. et al. microRNA-21 regulates astrocytic response following spinal cord injury. J. Neurosci. 32, 17935–17947 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Meares, G. P. et al. MicroRNA-31 is required for astrocyte specification. Glia 66, 987–998 (2018).

    PubMed  PubMed Central  Google Scholar 

  191. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Avansini, S. H. et al. Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia. Ann. Neurol. 83, 623–635 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Gorter, J. A. et al. Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol. Dis. 62, 508–520 (2014).

    CAS  PubMed  Google Scholar 

  194. Kretschmann, A. et al. Different microRNA profiles in chronic epilepsy versus acute seizure mouse models. J. Mol. Neurosci. 55, 466–479 (2015).

    CAS  PubMed  Google Scholar 

  195. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Parkhurst, C. N. et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Allen, N. J. & Lyons, D. A. Glia as architects of central nervous system formation and function. Science 362, 181–185 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

    CAS  PubMed  Google Scholar 

  199. 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).

    CAS  PubMed  Google Scholar 

  200. Choy, M. et al. A novel, noninvasive, predictive epilepsy biomarker with clinical potential. J. Neurosci. 34, 8672–8684 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. 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).

    CAS  PubMed  Google Scholar 

  202. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. 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.

    CAS  PubMed  Google Scholar 

  204. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 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).

    CAS  PubMed  Google Scholar 

  206. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 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).

    PubMed  PubMed Central  Google Scholar 

  208. 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).

    PubMed  PubMed Central  Google Scholar 

  209. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. McCoy, C. E. miR-155 dysregulation and therapeutic intervention in multiple sclerosis. Adv. Exp. Med. Biol. 1024, 111–131 (2017).

    CAS  PubMed  Google Scholar 

  211. Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).

    CAS  PubMed  Google Scholar 

  212. 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).

    CAS  PubMed  Google Scholar 

  213. Caballero-Garrido, E. et al. In vivo inhibition of miR-155 promotes recovery after experimental mouse stroke. J. Neurosci. 35, 12446–12464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Bruen, R., Fitzsimons, S. & Belton, O. miR-155 in the resolution of atherosclerosis. Front. Pharmacol. 10, 463 (2019).

    PubMed  PubMed Central  Google Scholar 

  215. 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).

    CAS  PubMed  Google Scholar 

  216. Fu, H. et al. Silencing microRNA-155 attenuates kainic acid-induced seizure by inhibiting microglia activation. Neuroimmunomodulation 26, 67–76 (2019).

    CAS  PubMed  Google Scholar 

  217. 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).

    CAS  PubMed  Google Scholar 

  218. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. 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).

    CAS  PubMed  Google Scholar 

  220. Jiang, X. et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog. Neurobiol. 163-164, 144–171 (2018).

    CAS  PubMed  Google Scholar 

  221. Ruber, T. et al. Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy. Brain 141, 2952–2965 (2018).

    PubMed  Google Scholar 

  222. 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).

    PubMed  Google Scholar 

  223. 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).

    CAS  PubMed  Google Scholar 

  224. Cheng, Y. D., Al-Khoury, L. & Zivin, J. A. Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 1, 36–45 (2004).

    PubMed  PubMed Central  Google Scholar 

  225. 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).

    PubMed  Google Scholar 

  226. 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.

    CAS  PubMed  Google Scholar 

  227. Franzoni, E. et al. miR-128 regulates neuronal migration, outgrowth and intrinsic excitability via the intellectual disability gene Phf6. eLife 4, e04263 (2015).

    PubMed Central  Google Scholar 

  228. Lee, S. T. et al. Inhibition of miR-203 reduces spontaneous recurrent seizures in mice. Mol. Neurobiol. 54, 3300–3308 (2017).

    CAS  PubMed  Google Scholar 

  229. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 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).

    CAS  PubMed  Google Scholar 

  231. Walker, M. C. & Kullmann, D. M. Optogenetic and chemogenetic therapies for epilepsy. Neuropharmacology 168, 107751 (2020).

    CAS  PubMed  Google Scholar 

  232. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Krutzfeldt, J. et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 438, 685–689 (2005).

    PubMed  Google Scholar 

  234. Braasch, D. A. & Corey, D. R. Locked nucleic acid (LNA): fine-tuning the recognition of DNA and RNA. Chem. Biol. 8, 1–7 (2001).

    CAS  PubMed  Google Scholar 

  235. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. 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).

    CAS  PubMed  Google Scholar 

  237. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. 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).

    CAS  PubMed  Google Scholar 

  239. Kim, J. et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N. Engl. J. Med. 381, 1644–1652 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Mollaei, H., Safaralizadeh, R. & Rostami, Z. MicroRNA replacement therapy in cancer. J. Cell. Physiol. 234, 12369–12384 (2019).

    CAS  PubMed  Google Scholar 

  242. van Gestel, M. A. et al. shRNA-induced saturation of the microRNA pathway in the rat brain. Gene Ther. 21, 205–211 (2014).

    PubMed  Google Scholar 

  243. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Zhan, L. et al. Protective role of miR-23b-3p in kainic acid-induced seizure. Neuroreport 27, 764–768 (2016).

    CAS  PubMed  Google Scholar 

  245. Sano, T. et al. MicroRNA-34a upregulation during seizure-induced neuronal death. Cell Death Dis. 3, e287 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Gan, J. et al. miR-96 attenuates status epilepticus-induced brain injury by directly targeting Atg7 and Atg16L1. Sci. Rep. 7, 10270 (2017).

    PubMed  PubMed Central  Google Scholar 

  248. 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).

    Google Scholar 

  249. 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).

    CAS  PubMed  Google Scholar 

  250. 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).

    CAS  PubMed  Google Scholar 

  251. Chen, L., Zheng, H. & Zhang, S. Involvement of upregulation of miR-210 in a rat epilepsy model. Neuropsychiatr. Dis. Treat. 12, 1731–1737 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Zheng, H. et al. MiR-219 protects against seizure in the kainic acid model of epilepsy. Mol. Neurobiol. 53, 1–7 (2016).

    CAS  PubMed  Google Scholar 

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI), Dublin, Ireland

    Gary P. Brennan & David C. Henshall

  2. FutureNeuro SFI Research Centre, RCSI, Dublin, Ireland

    Gary P. Brennan & David C. Henshall

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  1. Gary P. Brennan
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G.P.B. researched data for this article. Both authors made substantial contributions to discussion of the content, wrote the manuscript and reviewed and/or edited the manuscript before submission.

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Correspondence to David C. Henshall.

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Competing interests

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.

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Nature Reviews Neurology thanks H. Lerche, W. Lukiw and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

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.

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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

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