Neurochemical Research

, Volume 43, Issue 7, pp 1328–1338 | Cite as

The Expression Alteration of BC1 RNA and its Interaction with Eukaryotic Translation Initiation Factor eIF4A Post-Status Epilepticus

  • Xiangchang Zeng
  • Wenjing Zong
  • Qing Gao
  • Siyu Chen
  • Lulu Chen
  • Guirong Zeng
  • Weihua Huang
  • Zhenyu Li
  • Chang Zeng
  • Yuanyuan Xie
  • Xiaohui Li
  • Bo Xiao
  • Dongsheng-Ouyang
  • Kai Hu
Original Paper


Abnormal dendritic sprouting and synaptic remodelling are important pathological features of temporal lobe epilepsy. BC1 RNA is a translation repressor involved in the regulation of the dendritic protein synthesis and mRNA transport, which is essential for dendritic development and plasticity. The expression alteration of BC1 RNA in the pilocarpine induced epilepsy model remains unknown. It is unclear if the interactions between BC1 RNA and eukaryotic initiation factor 4A (eIF4A) exists in this model. The purpose of this study was to investigate the expression changes of BC1 RNA and its interactions with eIF4A post-status epilepticus (SE). Chloride lithium and pilocarpine were used to induce the SE rat model. Either a whole brain or hippocampus tissues were collected at different time points after SE. The expression patterns of BC1 was detected by qPCR and in situ hybridization. The levels of eIF4AI/II protein expression were analyzed via western blotting and immunohistochemistry. The BC1 RNA-eIF4AI/II interaction was determined by electrophoretic mobility shift assay (EMSA). We found that the BC1 RNA levels decreased in hippocampus 3d, 1w and 2w post-SE before the levels recovered. The eIF4AI/II began to rise 3d post-SE and reached the maximum level 1w post-SE. After 1w post-SE the levels decreased in the hippocampal CA1, CA3 and DG subregions. EMSA analysis showed that BC1 RNA specifically interacted with the eIF4AI/II. The BC1 RNA-eIF4AI/II complex reduced to the lowest level 1w post-SE. Our results suggested that BC1 has a negative regulatory correlation with eIF4AI/II, where BC1 RNA could be involved in epileptogenesis by regulating dendritic protein synthesis.


BC1 RNA eIF4AI/II Protein synthesis Status epilepticus Epileptogenesis 



Eukaryotic translation initiation factor AI/II


Status epilepticus


Electrophoretic mobility shift assay



This study was supported by the National Natural Science Foundation of China (Grant Nos: 81301106, 81371435 and 81671299), the Hunan Natural Science Foundation (Grant No.: 2016JC2057), Omics-based precision medicine of epilepsy being entrusted by Key Research Project of the Ministry of Science and Technology of China (Grant No.: 2016YFC0904400), the Xiangya Hospital Foundation (xywm2015I32).

Compliance with Ethical Standards

Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this paper.


  1. 1.
    Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, Sano T, O’Tuathaigh C, Waddington JL, Prenter S, Delanty N, Farrell MA, O’Brien DF, Conroy RM, Stallings RL, DeFelipe J, Henshall DC (2012) Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med 18:1087–1094CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Singh A, Trevick S (2016) The epidemiology of global epilepsy. Neurol Clin 34:837–847CrossRefPubMedGoogle Scholar
  3. 3.
    Kanner AM (2016) Management of psychiatric and neurological comorbidities in epilepsy. Nat Rev Neurol 12:106–116CrossRefPubMedGoogle Scholar
  4. 4.
    Houser CR (1999) Neuronal loss and synaptic reorganization in temporal lobe epilepsy. Adv Neurol 79:743–761PubMedGoogle Scholar
  5. 5.
    Cavazos JE, Jones SM, Cross DJ (2004) Sprouting and synaptic reorganization in the subiculum and CA1 region of the hippocampus in acute and chronic models of partial-onset epilepsy. Neuroscience 126:677–688CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Henshall DC, Kobow K (2015) Epigenetics and epilepsy. Cold Spring Harb Perspect Med 5:a022731CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Tongiorgi E, Armellin M, Giulianini PG, Bregola G, Zucchini S, Paradiso B, Steward O, Cattaneo A, Simonato M (2004) Brain-derived neurotrophic factor mRNA and protein are targeted to discrete dendritic laminas by events that trigger epileptogenesis. J Neurosci 24:6842–6852CrossRefPubMedGoogle Scholar
  8. 8.
    Stein JM, Bergman W, Fang Y, Davison L, Brensinger C, Robinson MB, Hecht NB, Abel T (2006) Behavioral and neurochemical alterations in mice lacking the RNA-binding protein translin. J Neurosci 26:2184–2196CrossRefPubMedGoogle Scholar
  9. 9.
    Garrido-Sanabria ER, Otalora LF, Arshadmansab MF, Herrera B, Francisco S, Ermolinsky BS (2008) Impaired expression and function of group II metabotropic glutamate receptors in pilocarpine-treated chronically epileptic rats. Brain Res 1240:165–176CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Heinrich C, Lahteinen S, Suzuki F, Anne-Marie L, Huber S, Haussler U, Haas C, Larmet Y, Castren E, Depaulis A (2011) Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis 42:35–47CrossRefPubMedGoogle Scholar
  11. 11.
    Bianchi R, Wong RKS, Merlin LR (2012) Glutamate receptors in epilepsy: group I mGluR-mediated epileptogenesis. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV (eds) Jasper’s basic mechanisms of the epilepsies. Bethesda, Oxford University PressGoogle Scholar
  12. 12.
    Merlin LR, Bergold PJ, Wong RK (1998) Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. J Neurophysiol 80:989–993CrossRefPubMedGoogle Scholar
  13. 13.
    Eom T, Zhang C, Wang H, Lay K, Fak J, Noebels JL, Darnell RB (2013) NOVA-dependent regulation of cryptic NMD exons controls synaptic protein levels after seizure. eLife 2:e00178CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Jimenez-Diaz L, Geranton SM, Passmore GM, Leith JL, Fisher AS, Berliocchi L, Sivasubramaniam AK, Sheasby A, Lumb BM, Hunt SP (2008) Local translation in primary afferent fibers regulates nociception. PLoS ONE 3:e1961CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Ben-Ari Y (2008) Epilepsies and neuronal plasticity: for better or for worse? Dialogues Clin Neurosci 10:17–27PubMedGoogle Scholar
  16. 16.
    Khlebodarova TM, Kogai VV, Trifonova EA, Likhoshvai VA (2017) Dynamic landscape of the local translation at activated synapses. Mol Psychiatry. PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Timofeev I, Bazhenov M, Avramescu S, Nita DA (2010) Posttraumatic epilepsy: the roles of synaptic plasticity. Neuroscientist 16:19–27CrossRefPubMedGoogle Scholar
  18. 18.
    Presutti C, Rosati J, Vincenti S, Nasi S (2006) Non coding RNA and brain. BMC Neurosci 7(Suppl 1):S5CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Cattani AA, Allene C, Seifert V, Rosenow F, Henshall DC, Freiman TM (2016) Involvement of microRNAs in epileptogenesis. Epilepsia 57:1015–1026CrossRefPubMedGoogle Scholar
  20. 20.
    Tiedge H, Fremeau RT Jr, Weinstock PH, Arancio O, Brosius J (1991) Dendritic location of neural BC1 RNA. Proc Natl Acad Sci USA 88:2093–2097CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang H, Iacoangeli A, Popp S, Muslimov IA, Imataka H, Sonenberg N, Lomakin IB, Tiedge H (2002) Dendritic BC1 RNA: functional role in regulation of translation initiation. J Neurosci 22:10232–10241CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Zhong J, Chuang SC, Bianchi R, Zhao W, Lee H, Fenton AA, Wong RK, Tiedge H (2009) BC1 regulation of metabotropic glutamate receptor-mediated neuronal excitability. J Neurosci 29:9977–9986CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Muslimov IA, Banker G, Brosius J, Tiedge H (1998) Activity-dependent regulation of dendritic BC1 RNA in hippocampal neurons in culture. J Cell Biol 141:1601–1611CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nimmrich V, Hargreaves EL, Muslimov IA, Bianchi R, Tiedge H (2005) Dendritic BC1 RNA: modulation by kindling-induced after discharges. Brain Res Mol Brain Res 133:110–118CrossRefPubMedGoogle Scholar
  25. 25.
    Skryabin BV, Sukonina V, Jordan U, Lewejohann L, Sachser N, Muslimov I, Tiedge H, Brosius J (2003) Neuronal untranslated BC1 RNA: targeted gene elimination in mice. Mol Cell Biol 23:6435–6441CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Gitai DL, Fachin AL, Mello SS, Elias CF, Bittencourt JC, Leite JP, Passos GA, Garcia-Cairasco N, Paco-Larson ML (2011) The non-coding RNA BC1 is down-regulated in the hippocampus of wistar audiogenic rat (WAR) strain after audiogenic kindling. Brain Res 1367:114–121CrossRefPubMedGoogle Scholar
  27. 27.
    Cavalheiro EA, Fernandes MJ, Turski L, Naffah-Mazzacoratti MG (1994) Spontaneous recurrent seizures in rats: amino acid and monoamine determination in the hippocampus. Epilepsia 35:1–11CrossRefPubMedGoogle Scholar
  28. 28.
    Curia G, Longo D, Biagini G, Jones RS, Avoli M (2008) The pilocarpine model of temporal lobe epilepsy. J Neurosci Methods 172:143–157CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Scorza FA, Arida RM, Naffah-Mazzacoratti Mda G, Scerni DA, Calderazzo L, Cavalheiro EA (2009) The pilocarpine model of epilepsy: what have we learned? Anais da Academia Brasileira de Ciencias 81:345–365CrossRefPubMedGoogle Scholar
  30. 30.
    Alsharafi WA, Xiao B, Li J (2016) MicroRNA-139-5p negatively regulates NR2A-containing NMDA receptor in the rat pilocarpine model and patients with temporal lobe epilepsy. Epilepsia 57:1931–1940CrossRefPubMedGoogle Scholar
  31. 31.
    Robeck T, Skryabin BV, Rozhdestvensky TS, Skryabin AB, Brosius J (2016) BC1 RNA motifs required for dendritic transport in vivo. Sci Rep 6:28300CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Murthy MR, Levesque G, Pandian S, Viallard JL, Ogier R, Cavagna AM, Dastugue B (1986) Isolation of free and membrane-bound polysomes and mRNA highly active in translation and reverse transcription from small discrete regions of rat brain. Neurochem Int 8:381–387CrossRefPubMedGoogle Scholar
  33. 33.
    Grifo JA, Tahara SM, Leis JP, Morgan MA, Shatkin AJ, Merrick WC (1982) Characterization of eukaryotic initiation factor 4A, a protein involved in ATP-dependent binding of globin mRNA. J Biol Chem 257:5246–5252PubMedGoogle Scholar
  34. 34.
    Grifo JA, Tahara SM, Morgan MA, Shatkin AJ, Merrick WC (1983) New initiation factor activity required for globin mRNA translation. J Biol Chem 258:5804–5810PubMedGoogle Scholar
  35. 35.
    Eom T, Berardi V, Zhong J, Risuleo G, Tiedge H (2011) Dual nature of translational control by regulatory BC RNAs. Mol Cell Biol 31:4538–4549CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Wang H, Iacoangeli A, Lin D, Williams K, Denman RB, Hellen CU, Tiedge H (2005) Dendritic BC1 RNA in translational control mechanisms. J Cell Biol 171:811–821CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Patel LS, Wenzel HJ, Schwartzkroin PA (2004) Physiological and morphological characterization of dentate granule cells in the p35 knock-out mouse hippocampus: evidence for an epileptic circuit. J Neurosci 24:9005–9014CrossRefPubMedGoogle Scholar
  38. 38.
    Bramham CR, Wells DG (2007) Dendritic mRNA: transport, translation and function. Nat Rev Neurosci 8:776–789CrossRefPubMedGoogle Scholar
  39. 39.
    Dahm R, Kiebler M, Macchi P (2007) RNA localisation in the nervous system. Semin Cell Dev Biol 18:216–223CrossRefPubMedGoogle Scholar
  40. 40.
    Cao X, Yeo G, Muotri AR, Kuwabara T, Gage FH (2006) Noncoding RNAs in the mammalian central nervous system. Annu Rev Neurosci 29:77–103CrossRefPubMedGoogle Scholar
  41. 41.
    Muslimov IA, Santi E, Homel P, Perini S, Higgins D, Tiedge H (1997) RNA transport in dendrites: a cis-acting targeting element is contained within neuronal BC1 RNA. J Neurosci 17:4722–4733CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Kondrashov AV, Kiefmann M, Ebnet K, Khanam T, Muddashetty RS, Brosius J (2005) Inhibitory effect of naked neural BC1 RNA or BC200 RNA on eukaryotic in vitro translation systems is reversed by poly(A)-binding protein (PABP). J Mol Biol 353:88–103CrossRefPubMedGoogle Scholar
  43. 43.
    Zalfa F, Giorgi M, Primerano B, Moro A, Di Penta A, Reis S, Oostra B, Bagni C (2003) The fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses. Cell 112:317–327CrossRefPubMedGoogle Scholar
  44. 44.
    Lacoux C, Di Marino D, Boyl PP, Zalfa F, Yan B, Ciotti MT, Falconi M, Urlaub H, Achsel T, Mougin A, Caizergues-Ferrer M, Bagni C (2012) BC1-FMRP interaction is modulated by 2′-O-methylation: RNA-binding activity of the tudor domain and translational regulation at synapses. Nucleic Acids Res 40:4086–4096CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kobayashi S, Kamo S, Ohmae A, Agui K, Li Y, Anzai K (2000) Identification of a negative regulatory DNA element for neuronal BC1 RNA expression by RNA polymerase III. Biochim Biophys 1493:142–150CrossRefGoogle Scholar
  46. 46.
    Centonze D, Rossi S, Napoli I, Mercaldo V, Lacoux C, Ferrari F, Ciotti MT, De Chiara V, Prosperetti C, Maccarrone M, Fezza F, Calabresi P, Bernardi G, Bagni C (2007) The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum. J Neurosci 27:8885–8892CrossRefPubMedGoogle Scholar
  47. 47.
    Maccarrone M, Rossi S, Bari M, De Chiara V, Rapino C, Musella A, Bernardi G, Bagni C, Centonze D (2010) Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA. Neuropsychopharmacology 35:1500–1509CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Zhong J, Chuang SC, Bianchi R, Zhao W, Paul G, Thakkar P, Liu D, Fenton AA, Wong RK, Tiedge H (2010) Regulatory BC1 RNA and the fragile X mental retardation protein: convergent functionality in brain. PLoS ONE 5:e15509CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Choi BY, Kim IY, Kim JH, Lee BE, Lee SH, Kho AR, Sohn M, Suh SW (2016) Zinc plus cyclo-(His-Pro) promotes hippocampal neurogenesis in rats. Neuroscience 339:634–643CrossRefPubMedGoogle Scholar
  50. 50.
    Ohno Y, Ishihara S, Terada R, Kikuta M, Sofue N, Kawai Y, Serikawa T, Sasa M (2009) Preferential increase in the hippocampal synaptic vesicle protein 2A (SV2A) by pentylenetetrazole kindling. Biochem Biophys Res Commun 390:415–420CrossRefPubMedGoogle Scholar
  51. 51.
    Shapiro LA, Figueroa-Aragon S, Ribak CE (2007) Newly generated granule cells show rapid neuroplastic changes in the adult rat dentate gyrus during the first five days following pilocarpine-induced seizures. Eur J Neurosci 26:583–592CrossRefPubMedGoogle Scholar
  52. 52.
    Arkhipov VI, Kapralova MV (2014) Expression of metabotropic glutamate receptors after hippocampal injury. Bull Exp Biol Med 156:457–460CrossRefPubMedGoogle Scholar
  53. 53.
    Kapp LD, Lorsch JR (2004) The molecular mechanics of eukaryotic translation. Annu Rev Biochem 73:657–704CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Xiangchang Zeng
    • 1
    • 2
  • Wenjing Zong
    • 1
    • 2
  • Qing Gao
    • 1
    • 2
  • Siyu Chen
    • 1
    • 2
  • Lulu Chen
    • 1
    • 2
  • Guirong Zeng
    • 4
  • Weihua Huang
    • 1
    • 2
  • Zhenyu Li
    • 5
  • Chang Zeng
    • 6
  • Yuanyuan Xie
    • 3
  • Xiaohui Li
    • 7
  • Bo Xiao
    • 3
  • Dongsheng-Ouyang
    • 1
    • 2
  • Kai Hu
    • 3
  1. 1.Department of Clinical Pharmacology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  2. 2.Institute of Clinical Pharmacology, Hunan Key Laboratory of PharmacogeneticsCentral South UniversityChangshaPeople’s Republic of China
  3. 3.Department of Neurology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  4. 4.Hunan Key Laboratory of Pharmacodynamics and Safety Evaluation of New Drugs & Hunan Provincial Research Center for Safety Evaluation of DrugsChangshaPeople’s Republic of China
  5. 5.Department of Cardiology, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  6. 6.Health Management Center, Xiangya HospitalCentral South UniversityChangshaPeople’s Republic of China
  7. 7.Department of Pharmacology, School of Pharmaceutical ScienceCentral South UniversityChangshaPeople’s Republic of China

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