Skip to main content
SpringerLink
Log in

Endogenous serotonin facilitates hippocampal long-term potentiation at CA3/CA1 synapses

  • Translational Neurosciences - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Encoding of episodic memory requires long-term potentiation (LTP) of neurotransmission at excitatory synapses of the hippocampal circuitry. Previous data obtained with the application of exogenous 5-hydroxytryptamine (5-HT) in hippocampal slices indicate that 5-HT blocks LTP, which contrasts with the facilitatory effect of selective serotonin reuptake inhibitors (SSRIs) on learning and memory observed in vivo. Here, we investigated the effects of endogenous 5-HT, released from terminals by the monoamine releaser 3,4-methylenedioxymethamphetamine (MDMA), on LTP of field EPSPs induced by theta-burst stimulation and recorded at CA3/CA1 synapses of rat hippocampal slices. LTP was greater in the presence of MDMA (10 µM; 45.76 ± 15.75 %; n = 28) than in controls (31.26 ± 11.03; n = 21; p < 0.01). This facilitatory effect on LTP persisted when the entry of MDMA in noradrenergic terminals was prevented by the selective noradrenaline reuptake inhibitor nisoxetine (44.90 ± 14.07 %; n = 27 vs. 34.49 ± 12.94 %; n = 20 in controls; p < 0.05). In both conditions, the facilitation of LTP was abolished by the SSRI citalopram that prevented the entry of MDMA in 5-HT terminals and the subsequent 5-HT release. These data show that, unlike exogenous 5-HT application, release of endogenous 5-HT does not impair cellular mechanisms responsible for induction of LTP, indicating that 5-HT is not detrimental to learning and memory. Moreover, facilitation of LTP by endogenous 5-HT may underlie the in vivo positive effects of augmented 5-HT tone on cognitive performance.

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

Access this article

Log in via an institution

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

  • Abad S, Fole A, Del Olmo N, Pubill D, Pallàs M, Junyent F, Camarasa J, Camins A, Escubedo E (2014) MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density. Psychopharmacology (Berl). Psychopharmacology 231(5):863–874

    Article  CAS  PubMed  Google Scholar 

  • Anderson IM, Juhasz G, Thomas E, Downey D, McKie S, Deakin JF, Elliott R (2011) The effect of acute citalopram on face emotion processing in remitted depression: a pharmacoMRI study. Eur Neuropsychopharmacol 21(1):140–148

    Article  CAS  PubMed  Google Scholar 

  • Andrade R, Beck SG (2010) Cellular effects of serotonin in the CNS. In: Muller CP, Jacobs B (eds) Handbook of the behavioral neurobiology of serotonin. Academic Press, London, pp 219–231

    Chapter  Google Scholar 

  • Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38(8):1083–1152

    Article  CAS  PubMed  Google Scholar 

  • Bliss TVP, Goddard GV, Riives M (1983) Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines. J Physiol (London) 334:475–491

    Article  CAS  Google Scholar 

  • Bliss TVP, Collingridge GL, Morris R (2007) Synaptic plasticity in the hippocampus. In: Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J (eds) The hippocampus book. Oxford University Press Inc, New York, pp 343–474

    Google Scholar 

  • Corradetti R, Ballerini L, Pugliese AM, Pepeu G (1992) Serotonin blocks the long-term potentiation induced by primed burst stimulation in the CA1 region of rat hippocampal slices. Neuroscience 46:511–518

    Article  CAS  PubMed  Google Scholar 

  • Del-Ben CM, Ferreira CA, Alves-Neto WC, Graeff FG (2008) Serotonergic modulation of face-emotion recognition. Braz J Med Biol Res 41:263–269

    Article  CAS  PubMed  Google Scholar 

  • Elliott R, Zahn R, Deakin JF, Anderson IM (2011) Affective cognition and its disruption in mood disorders. Neuropsychopharmacology 36(1):153–182

    Article  PubMed Central  PubMed  Google Scholar 

  • Fitzgerald JL, Reid JJ (1993) Interactions of methylenedioxymethamphetamine with monoamine transmitter release mechanisms in rat brain slices. Naunyn Schmiedebergs Arch Pharmacol 347:313–323

    Article  CAS  PubMed  Google Scholar 

  • Garrett AS, Maddock RJ (2006) Separating subjective emotion from the perception of emotion-inducing stimuli: an fMRI study. Neuroimage 33:263–274

    Article  PubMed  Google Scholar 

  • Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM (2002) Acute administration of citalopram facilitates memory consolidation in healthy volunteers. Psychopharmacology 163:106–110

    Article  CAS  PubMed  Google Scholar 

  • Harmer CJ, Bhagwagar Z, Perrett DI, Völlm BA, Cowen PJ, Goodwin GM (2003) Acute SSRI administration affects the processing of social cues in healthy volunteers. Neuropsychopharmacology 28(1):148–152

    Article  CAS  PubMed  Google Scholar 

  • Hayward G, Goodwin GM, Cowen PJ, Harmer CJ (2005) Low-dose tryptophan depletion in recovered depressed patients induces changes in cognitive processing without depressive symptoms. Biol Psychiatry 57(5):517–524

    Article  CAS  PubMed  Google Scholar 

  • Hensler JG (2006) Serotonergic modulation of the limbic system. Neurosci Biobehav Rev 30(2):203–214

    Article  CAS  PubMed  Google Scholar 

  • Hyttel J, Larsen JJ (1985) Neurochemical profile of Lu 19-005, a potent inhibitor of uptake of dopamine, noradrenaline, and serotonin. J Neurochem 44:1615–1622

    Article  CAS  PubMed  Google Scholar 

  • Izquierdo I, Medina JH (1995) Correlation between the pharmacology of long-term potentiation and the pharmacology of memory. Neurobiol Learn Mem 63(1):19–32

    Article  CAS  PubMed  Google Scholar 

  • Jahnsen H (1980) The action of 5-hydroxytryptamine on neuronal membranes and synaptic transmission in area CA1 of the hippocampus in vitro. Brain Res 197:83–94

    Article  CAS  PubMed  Google Scholar 

  • Jensen O, Lisman JE (2005) Hippocampal sequence-encoding driven by a cortical multi-item working memory buffer. Trends Neurosci 28(2):67–72

    Article  CAS  PubMed  Google Scholar 

  • Johnston D, Wu SMS (1995) Extracellular field recordings. In: Johnston D, Wu SMS (eds) Foundations of cellular neurophysiology. MIT Press, Cambridge, pp 423–439

    Google Scholar 

  • Klancnik JM, Phillips AG (1991) Modulation of synaptic plasticity in the dentate gyrus of the rat by electrical stimulation of the median raphe nucleus. Brain Res 557(1–2):236–240

    Article  CAS  PubMed  Google Scholar 

  • Kuypers KP, Ramaekers JG (2007) Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected. Psychopharmacology 189(4):557–563

    Article  CAS  PubMed  Google Scholar 

  • Larson J, Lynch G (1986) Induction of synaptic potentiation in hippocampus by patterned stimulation involves two events. Science 232:985–988

    Article  CAS  PubMed  Google Scholar 

  • Lesch KP, Waider J (2012) Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 76(1):175–191

    Article  CAS  PubMed  Google Scholar 

  • McKie S, Del-Ben C, Elliott R, Williams S, del Vai N, Anderson I, Deakin JF (2005) Neuronal effects of acute citalopram detected by pharmacoMRI. Psychopharmacology 180(4):680–686

    Article  CAS  PubMed  Google Scholar 

  • Mlinar B, Corradetti R (2003) Endogenous 5-HT, released by MDMA through serotonin transporter- and secretory vesicle-dependent mechanisms, reduces hippocampal excitatory synaptic transmission by preferential activation of 5-HT1B receptors located on CA1 pyramidal neurons. Eur J Neurosci 18:1559–1571

    Article  PubMed  Google Scholar 

  • Mlinar B, Mascalchi S, Morini R, Giachi F, Corradetti R (2008) MDMA induces EPSP-Spike potentiation in rat ventral hippocampus in vitro via serotonin and noradrenaline release and coactivation of 5-HT4 and beta1 receptors. Neuropsychopharmacology 33:1464–1475

    Article  CAS  PubMed  Google Scholar 

  • Morini R, Mlinar B, Baccini G, Corradetti R (2011) Enhanced hippocampal long-term potentiation following repeated MDMA treatment in Dark-Agouti rats. Eur Neuropsychopharmacol 21:80–91

    Article  CAS  PubMed  Google Scholar 

  • Moyano S, Frechilla D, Del Río J (2004) NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment. Psychopharmacology 173(3–4):337–345

    Article  CAS  PubMed  Google Scholar 

  • Otto T, Eichenbaum H, Wiener SI, Wible CG (1991) Learning-related patterns of CA1 spike trains parallel stimulation parameters optimal for inducing hippocampal long-term potentiation. Hippocampus 1:181–192

    Article  CAS  PubMed  Google Scholar 

  • Pugliese AM, Ballerini L, Passani MB, Corradetti R (1994) EPSP-Spike potentiation during primed burst-induced long-term potentiation in the CA1 region of rat hippocampal slices. Neuroscience 62:1021–1032

    Article  CAS  PubMed  Google Scholar 

  • Pugliese AM, Passani MB, Corradetti R (1998) Effect of the selective 5-HT1A receptor antagonist WAY 100635 on the inhibition of e.p.s.ps produced by 5-HT in the CA1 region of rat hippocampal slices. Br J Pharmacol 124(1):93–100

    Article  CAS  PubMed  Google Scholar 

  • Richter-Levin G, Segal M (1991) The effects of serotonin depletion and raphe grafts on hippocampal electrophysiology and behavior. J Neurosci 11(6):1585–1596

    CAS  PubMed  Google Scholar 

  • Rodsiri R, Spicer C, Green AR, Marsden CA, Fone KC (2011) Acute concomitant effects of MDMA binge dosing on extracellular 5-HT, locomotion and body temperature and the long-term effect on novel object discrimination in rats. Psychopharmacology 213(2–3):365–376

    Article  CAS  PubMed  Google Scholar 

  • Ropert N (1988) Inhibitory action of serotonin in CA1 hippocampal neurons in vitro. Neuroscience 26:69–81

    Article  CAS  PubMed  Google Scholar 

  • Rozas C, Loyola S, Ugarte G, Zeise ML, Reyes-Parada M, Pancetti F, Rojas P, Morales B (2012) Acutely applied MDMA enhances long-term potentiation in rat hippocampus involving D1/D5 and 5-HT2 receptors through a polysynaptic mechanism. Eur Neuropsychopharmacol 22(8):584–595

    Article  CAS  PubMed  Google Scholar 

  • Rudnick G, Wall SC (1992) The molecular mechanism of ‘ecstasy’ [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Proc Natl Acad Sci USA 89:1817–1821

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Schaefer HS, Putnam KM, Benca RM, Davidson RJ (2006) Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression. Biol Psychiatry 60:974–986

    Article  PubMed  Google Scholar 

  • Segal M (1980) The action of serotonin in the hippocampal slice preparation. J Physiol (London) 303:423–439

    Article  CAS  Google Scholar 

  • Sitte HH, Scholze P, Schloss P, Pifl C, Singer EA (2000) Characterization of carrier-mediated efflux in human embryonic kidney 293 cells stably expressing the rat serotonin transporter: a superfusion study. J Neurochem 74:1317–1324

    Article  CAS  PubMed  Google Scholar 

  • Staubli U, Otaky N (1994) Serotonin controls the magnitude of LTP induced by theta bursts via an action on NMDA- receptor-mediated responses. Brain Res 643:10–16

    Article  CAS  PubMed  Google Scholar 

  • Stough C, King R, Papafotiou K, Swann P, Ogden E, Wesnes K, Downey LA (2012) The acute effects of 3,4-methylenedioxymethamphetamine and d-methamphetamine on human cognitive functioning. Psychopharmacology 220(4):799–807

    Article  CAS  PubMed  Google Scholar 

  • Tse WS, Bond AJ (2002) Serotonergic intervention affects both social dominance and affiliative behaviour. Psychopharmacology 161(3):324–330

    Article  CAS  PubMed  Google Scholar 

  • van der Veen FM, Evers EA, van Deursen JA, Deutz NE, Backesm WH, Schmitt JA (2006) Acute tryptophan depletion reduces activation in the right hippocampus during encoding in an episodic memory task. Neuroimage 31(3):1188–1196

    Article  PubMed  Google Scholar 

  • Villani F, Johnston D (1993) Serotonin inhibits induction of long-term potentiation at commissural synapses in hippocampus. Brain Res 606:304–308

    Article  CAS  PubMed  Google Scholar 

  • Wang SH, Morris RG (2010) Hippocampal-neocortical interactions in memory formation, consolidation, and reconsolidation. Annu Rev Psychol 61(49–79):C1–C4

    Google Scholar 

  • Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science 313:1093–1097

    Article  CAS  PubMed  Google Scholar 

  • Winterer J, Stempel AV, Dugladze T, Földy C, Maziashvili N, Zivkovic AR, Priller J, Soltesz I, Gloveli T, Schmitz D (2011) Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus. J Neurosci 31(23):8464–8475

    Article  CAS  PubMed  Google Scholar 

  • Young SN, Leyton M (2002) The role of serotonin in human mood and social interaction Insight from altered tryptophan levels. Pharmacol Biochem Behav 71(4):857–865

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Funding for this study was provided by European Commission Grants (Ecstasy damage: QLG3-CT2002-00809 and Newmood: LSHM-CT-2004-503474).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Author notes

  1. Gabriella Stocca

    Present address: Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland

Authors and Affiliations

  1. Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini 6, 50139, Florence, Italy

    Boris Mlinar, Gabriella Stocca & Renato Corradetti

Authors
  1. Boris Mlinar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gabriella Stocca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renato Corradetti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Renato Corradetti.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mlinar, B., Stocca, G. & Corradetti, R. Endogenous serotonin facilitates hippocampal long-term potentiation at CA3/CA1 synapses. J Neural Transm 122, 177–185 (2015). https://doi.org/10.1007/s00702-014-1246-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-014-1246-7

Keywords

Search

Navigation