Skip to main content
Log in

Long-term decrease in immediate early gene expression after electroconvulsive seizures

  • Basic Neurosciences, Genetics and Immunology - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Electroconvulsive therapy (ECT) is a well-established psychiatric treatment for severe depression. Despite its clinical utility, post-ECT memory deficits are a common side effect. Neuronal plasticity and memory consolidation are intimately related to the expression of immediate early genes (IEG), such as Egr1, Fos and Arc. Changes in IEG activation have been postulated to underlie long-term neuronal adaptations following electroconvulsive seizures (ECS), an animal model of ECT. To test this hypothesis, we used real-time PCR to examine the effect of acute and chronic ECS (8 sessions, one every other day) on the long-term (>24 h) expression of IEG Egr1, Fos and Arc in the hippocampus, a brain region implicated both in the pathophysiology of depression as well as in memory function. We observed a transient increase in Egr1 and Fos expression immediately after ECS, followed by a long-term decrease of IEG levels after both acute and chronic ECS. A separate group of animals, submitted to the same chronic ECS protocol and then subjected to open field or passive avoidance tasks, confirmed robust memory deficits 2 weeks after the last chronic ECS. The possible role of IEG downregulation on long-term learning deficits observed following ECS are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Barichello T, Bonatto F, Agostinho FR, Reinke A, Moreira JCF, Dal-Pizzol F et al (2004) Structure-related oxidative damage in rat brain after acute and chronic electroshock. Neurochem Res 29:1749–1753

    Article  PubMed  CAS  Google Scholar 

  • Bohbot V, Otahal P, Liu Z, Nadel L, Bures J (1996) Electroconvulsive shock and lidocaine reveal rapid consolidation of spatial working memory in the water maze. Proc Natl Acad Sci USA 93:4016–4019

    Article  PubMed  CAS  Google Scholar 

  • Chaudhuri An (1997) Neural activity mapping with inducible transcription factors. Neuroreport 8:iii–vii

  • Clayton DF (2000) The genomic action potential. Neurobiol Learn Mem 74:185–216

    Article  PubMed  CAS  Google Scholar 

  • Falconer DW, Cleland J, Fielding S, Reid IC (2010) Using the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess the cognitive impact of electroconvulsive therapy on visual and visuospatial memory. Psychol Med 40:1017–1025

    Article  PubMed  CAS  Google Scholar 

  • Fleischmann A, Hvalby O, Jensen V, Strekalova T, Zacher C, Layer LE et al (2003) Impaired long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS. J Neurosci 23:9116–9122

    PubMed  CAS  Google Scholar 

  • Gil GA, Bussolino DF, Portal MM, Pecchio AA, Renner ML, Borioli GA et al (2004) c-Fos activated phospholipid synthesis is required for neurite elongation in differentiating PC12 cells. Mol Biol Cell 15:1881–1894

    Article  PubMed  CAS  Google Scholar 

  • Grimm R, Tischmeyer W (1997) Complex patterns of immediate early gene induction in rat brain following brightness discrimination training and pseudotraining. Behav Brain Res 84:109–116

    Article  PubMed  CAS  Google Scholar 

  • Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF et al (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20:3993–4001

    PubMed  CAS  Google Scholar 

  • Herdegen T, Leah JD (1998) Inducible and constitutive transcription factors in the mammalian nervous system: control of gene expression by Jun, Fos and Krox, and CREB/ATF proteins. Brain Res Brain Res Rev 28:370–490

    Article  PubMed  CAS  Google Scholar 

  • Hernandez PJ, Schiltz CA, Kelley AE (2006) Dynamic shifts in corticostriatal expression patterns of the immediate early genes Homer 1a and Zif268 during early and late phases of instrumental training. Learn Mem 13:599–608

    Article  PubMed  CAS  Google Scholar 

  • Hope BT, Kelz MB, Duman RS, Nestler EJ (1994) Chronic electroconvulsive seizure (ECS) treatment results in expression of a long-lasting AP-1 complex in brain with altered composition and characteristics. J Neurosci 14:4318–4328

    PubMed  CAS  Google Scholar 

  • Jones MW, Errington ML, French PJ, Fine A, Bliss TV, Garel S et al (2001) A requirement for the immediate early gene Zif268 in the expression of late LTP and long-term memories. Nat Neurosci 4:289–296

    Article  PubMed  CAS  Google Scholar 

  • Jung HY, Kang UG, Ahn YM, Joo YH, Park JB, Kim YS (1996) Induction of tetradecanoyl phorbol acetate-inducible sequence (TIS) genes by electroconvulsive shock in rat brain. Biol Psychiatry 40:503–507

    Article  PubMed  CAS  Google Scholar 

  • Knapska E, Kaczmarek L (2004) A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK? Prog Neurobiol 74:183–211

    Article  PubMed  CAS  Google Scholar 

  • Lanahan A, Lyford G, Stevenson GS, Worley PF, Barnes CA (1997) Selective alteration of long-term potentiation-induced transcriptional response in hippocampus of aged, memory-impaired rats. J Neurosci 17:2876–2885

    PubMed  CAS  Google Scholar 

  • Larsen MH, Olesen M, Woldbye DP, Hay-Schmidt A, Hansen HH, Ronn LC et al (2005) Regulation of activity-regulated cytoskeleton protein (Arc) mRNA after acute and chronic electroconvulsive stimulation in the rat. Brain Res 1064:161–165

    Article  PubMed  CAS  Google Scholar 

  • Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U et al (1995) Somatodendritic expression of an immediate early gene is regulated by synaptic activity. Proc Natl Acad Sci USA 92:5734–5738

    Article  PubMed  CAS  Google Scholar 

  • Lisanby SH (2007) Electroconvulsive therapy for depression. N Engl J Med 357:1939–1945

    Article  PubMed  CAS  Google Scholar 

  • Lisanby SH, Maddox JH, Prudic J, Devanand DP, Sackeim HA (2000) The effects of electroconvulsive therapy on memory of autobiographical and public events. Arch Gen Psychiatry 57:581–590

    Article  PubMed  CAS  Google Scholar 

  • McDaniel WW, Sahota AK, Vyas BV, Laguerta N, Hategan L, Oswald J (2006) Ketamine appears associated with better word recall than etomidate after a course of 6 electroconvulsive therapies. J Ect 22:103–106

    Article  PubMed  CAS  Google Scholar 

  • Morinobu S, Strausbaugh H, Terwilliger R, Duman RS (1997) Regulation of c-Fos and NGF1-A by antidepressant treatments. Synapse 25:313–320

    Article  PubMed  CAS  Google Scholar 

  • National Institutes of Health (1985) Electroconvulsive therapy. NIH Consensus Statement Online, NIH, Bethesda, June 10–12 [cited year month day], vol 5(11), pp 1–23. http://www.consensus.nih.gov/1985/1985ElectroconvulsiveTherapy051html.htm

  • Nikolaev E, Kaminska B, Tischmeyer W, Matthies H, Kaczmarek L (1992) Induction of expression of genes encoding transcription factors in the rat brain elicited by behavioral training. Brain Res Bull 28:479–484

    Article  PubMed  CAS  Google Scholar 

  • Nobler MS, Sackeim HA (2008) Neurobiological correlates of the cognitive side effects of electroconvulsive therapy. J Ect 24:40–45

    Article  PubMed  Google Scholar 

  • O’Donovan KJ, Wilkens EP, Baraban JM (1998) Sequential expression of Egr-1 and Egr-3 in hippocampal granule cells following electroconvulsive stimulation. J Neurochem 70:1241–1248

    Article  PubMed  Google Scholar 

  • Pfaffl MW (2004) Quantification strategies in real-time PCR. In: Bustin SA (ed) A–Z of quantitative PCR. International University Line (IUL), La Jolla, pp 87–112

  • Rapanelli M, Frick LR, Zanutto BS (2009) Differential gene expression in the rat hippocampus during learning of an operant conditioning task. Neuroscience 163:1031–1038

    Google Scholar 

  • Reus GZ, Valvassori SS, Machado RA, Martins MR, Gavioli EC, Quevedo J (2008) Acute treatment with low doses of memantine does not impair aversive, non-associative and recognition memory in rats. Naunyn Schmiedebergs Arch Pharmacol 376:295–300

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro S, Gervasoni D, Soares ES, Zhou Y, Lin SC, Pantoja J et al (2004) Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas. PLoS Biol 2:126–137

    Article  Google Scholar 

  • Ronnback A, Dahlqvist P, Bergstrom SA, Olsson T (2005) Diurnal effects of enriched environment on immediate early gene expression in the rat brain. Brain Res 1046:137–144

    Article  PubMed  Google Scholar 

  • Rose D, Fleischmann P, Wykes T, Leese M, Bindman J (2003) Patients’ perspectives on electroconvulsive therapy: systematic review. BMJ 326:1363

    Article  PubMed  Google Scholar 

  • Sackeim HA, Prudic J, Fuller R, Keilp J, Lavori PW, Olfson M (2007) The cognitive effects of electroconvulsive therapy in community settings. Neuropsychopharmacology 32:244–254

    Article  PubMed  Google Scholar 

  • Sanchez Gonzalez R, Alcoverro O, Pagerols J, Rojo JE (2009) Electrophysiological mechanisms of action of electroconvulsive therapy. Actas Esp Psiquiatr 37:343–351

    PubMed  Google Scholar 

  • Smith GE, Rasmussen KG Jr, Cullum CM, Felmlee-Devine MD, Petrides G, Rummans TA et al (2010) A randomized controlled trial comparing the memory effects of continuation electroconvulsive therapy versus continuation pharmacotherapy: results from the Consortium for Research in ECT (CORE) study. J Clin Psychiatry 71:185–193

    Article  PubMed  Google Scholar 

  • Sng JC, Taniura H, Yoneda Y (2004) A tale of early response genes. Biol Pharm Bull 27:606–612

    Article  PubMed  CAS  Google Scholar 

  • Squire LR (1986) Memory functions as affected by electroconvulsive therapy. Ann N Y Acad Sci 462:307–314

    Article  PubMed  CAS  Google Scholar 

  • Trepel C, Racine RJ (1999) Blockade and disruption of neocortical long-term potentiation following electroconvulsive shock in the adult, freely moving rat. Cereb Cortex 9:300–305

    Article  PubMed  CAS  Google Scholar 

  • Tsankova NM, Kumar A, Nestler EJ (2004) Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J Neurosci 24:5603–5610

    Article  PubMed  CAS  Google Scholar 

  • Tzingounis AV, Nicoll RA (2006) Arc/Arg3.1: linking gene expression to synaptic plasticity and memory. Neuron 52:403–407

    Article  PubMed  CAS  Google Scholar 

  • Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al (2002) Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 3:RESEARCH0034

    Google Scholar 

  • Wallace CS, Lyford GL, Worley PF, Steward O (1998) Differential intracellular sorting of immediate early gene mRNAs depends on signals in the mRNA sequence. J Neurosci 18:26–35

    PubMed  CAS  Google Scholar 

  • Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G et al (2001) Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation. J Neurosci 21:5484–5493

    PubMed  CAS  Google Scholar 

  • Watanabe Y, Johnson RS, Butler LS, Binder DK, Spiegelman BM, Papaioannou VE et al (1996) Null mutation of c-Fos impairs structural and functional plasticities in the kindling model of epilepsy. J Neurosci 16:3827–3836

    PubMed  CAS  Google Scholar 

  • Weeks D, Freeman CP, Kendell RE (1980) ECT: III: enduring cognitive deficits? Br J Psychiatry 137:26–37

    Article  PubMed  CAS  Google Scholar 

  • Willems E, Leyns L, Vandesompele J (2008) Standardization of real-time PCR gene expression data from independent biological replicates. Anal Biochem 379:127–129

    Article  PubMed  CAS  Google Scholar 

  • Winston SM, Hayward MD, Nestler EJ, Duman RS (1990) Chronic electroconvulsive seizures down-regulate expression of the immediate-early genes c-fos and c-jun in rat cerebral cortex. J Neurochem 54:1920–1925

    Article  PubMed  CAS  Google Scholar 

  • Wisden W, Errington ML, Williams S, Dunnett SB, Waters C, Hitchcock D et al (1990) Differential expression of immediate early genes in the hippocampus and spinal cord. Neuron 4:603–614

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Council of Technological and Scientific Development (CNPq), the Coordination for the Improvement of Higher Level Personnel (Capes), Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS), and the State of São Paulo Research Foundation (FAPESP).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Samira S. Valvassori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calais, J.B., Valvassori, S.S., Resende, W.R. et al. Long-term decrease in immediate early gene expression after electroconvulsive seizures. J Neural Transm 120, 259–266 (2013). https://doi.org/10.1007/s00702-012-0861-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-012-0861-4

Keywords

Navigation