Regulation of the Serotonergic System by Kainate in the Avian Retina

  • Adelaide da Conceição Fonseca Passos
  • Anderson Manoel Herculano
  • Karen R. H. M. Oliveira
  • Silene Maria A. de Lima
  • Fernando A. F. Rocha
  • Hércules Rezende Freitas
  • Luzia da Silva Sampaio
  • Danniel Pereira Figueiredo
  • Karin da Costa Calaza
  • Ricardo Augusto de Melo Reis
  • José Luiz Martins do NascimentoEmail author
Original Research


Serotonin (5-HT) has been recognized as a neurotransmitter in the vertebrate retina, restricted mainly to amacrine and bipolar cells. It is involved with synaptic processing and possibly as a mitogenic factor. We confirm that chick retina amacrine and bipolar cells are, respectively, heavily and faintly immunolabeled for 5-HT. Amacrine serotonergic cells also co-express tyrosine hydroxylase (TH), a marker of dopaminergic cells in the retina. Previous reports demonstrated that serotonin transport can be modulated by neurotransmitter receptor activation. As 5-HT is diffusely released as a neuromodulator and co-localized with other transmitters, we evaluated if 5-HT uptake or release is modulated by several mediators in the avian retina. The role of different glutamate receptors on serotonin transport and release in vitro and in vivo was also studied. We show that l-glutamate induces an inhibitory effect on [3H]5-HT uptake and this effect was specific to kainate receptor activation. Kainate-induced decrease in [3H]5-HT uptake was blocked by CNQX, an AMPA/kainate receptor antagonist, but not by MK-801, a NMDA receptor antagonist. [3H]5-HT uptake was not observed in the presence of AMPA, thus suggesting that the decrease in serotonin uptake is mediated by kainate. 5-HT (10–50 μM) had no intrinsic activity in raising intracellular Ca2+, but addition of 10 μM 5-HT decreased Ca2+ shifts induced by KCl in retinal neurons. Moreover, kainate decreased the number of bipolar and amacrine cells labeled to serotonin in chick retina. In conclusion, our data suggest a highly selective effect of kainate receptors in the regulation of serotonin functions in the retinal cells.


Serotonin Glutamate receptors Retina Kainate 



Grants from Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional (INCT-INNT), Instituto Nacional de Ciência e Tecnologia de Neuroimodulação (INCT-NIM), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) supported this work. DPF thanks CAPES/Brazil for doctoral fellowships. JLMN and AMH thank CNPQ for the individual research fellowship. KCC and RAMR thank CNPq and FAPERJ for the individual research fellowship. We thank Granja Americano (Santa Izabel Alimento LTDA) for kindly providing Fertilized White Leghorn eggs (Gallus gallus) for our experiments.

Author Contributions

Conceived and designed the experiments: LSS, HRF, KCC, RAMR, and JLMN. Performed the experiments: ACFP, SMAL, LSS, HRF, FAFR, and DPF. Analyzed the data: AMH, KRHMO, KCC, RAMR, and JLMN. Contributed reagents/materials/analysis tools: KCC, RAMR, and JLMN. Wrote the paper and financial support and administrative support: KCC, RAMR, and JLMN.


This study was funded by CNPq (Grant number 552491/2011-0).

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

All experiments involving animals were approved and carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Federal University of Pará (permit number 85/15) and Federal University of Rio de Janeiro (permit number IBCCF-035).


  1. Amara SG, Kuhar MJ (1993) Neurotransmitter transporters: recent progress. Annu Rev Neurosci 16:73–93CrossRefGoogle Scholar
  2. Beart PM (2016) Synaptic signalling and its interface with neuropathologies: snapshots from the past, present and future. J Neurochem 139(Suppl 2):76–90CrossRefGoogle Scholar
  3. Beckman ML, Bernstein EM, Quick MW (1999) Multiple G protein-coupled receptors initiate protein kinase C redistribution of GABA transporters in hippocampal neurons. J Neurosci 19(11):RC9CrossRefGoogle Scholar
  4. Blakely RD, Berson HE, Fremeau RT Jr, Caron MG, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter from rat brain. Nature 354:66–70CrossRefGoogle Scholar
  5. Borghuis BG, Looger LL, Tomita S, Demb JB (2014) Kainate receptors mediate signaling in both transient and sustained OFF bipolar cell pathways in mouse retina. J Neurosci 34:6128–6139CrossRefGoogle Scholar
  6. Brandstatter JH, Koulen P, Wassle H (1997) Selective synaptic distribution of kainate receptor subunits in the two plexiform layers of the rat retina. J Neurosci 17:9298–9307CrossRefGoogle Scholar
  7. Calaza KC, de Mello FG, Gardino PF (2001) GABA release induced by aspartate-mediated activation of NMDA receptors is modulated by dopamine in a selective subpopulation of amacrine cells. J Neurocytol 30:181–193CrossRefGoogle Scholar
  8. Ciranna L (2006) Serotonin as a modulator of glutamate- and GABA-mediated neurotransmission: implications in physiological functions and in pathology. Curr Neuropharmacol 4(2):101–114CrossRefGoogle Scholar
  9. Connaughton, V., 1995. Glutamate and Glutamate Receptors in the Vertebrate Retina, In: Kolb, H., Fernandez, E., Nelson, R. (Eds.), Webvision: The Organization of the Retina and Visual System,University of Utah Health Sciences Center, Salt Lake City (UT)Google Scholar
  10. da Silva Sampaio L, Kubrusly RCC, Colli YP, Trindade PP, Ribeiro-Resende VT, Einicker-Lamas M, Paes-de-Carvalho R, Gardino PF, de Mello FG, De Melo Reis RA (2018) Cannabinoid receptor type 1 expression in the developing avian retina: morphological and functional correlation with the dopaminergic system. Front Cell Neurosci 12:58CrossRefGoogle Scholar
  11. De Melo Reis RA, Schitine CS, Kofalvi A, Grade S, Cortes L, Gardino PF, Malva JO, de Mello FG (2011) Functional identification of cell phenotypes differentiating from mice retinal neurospheres using single cell calcium imaging. Cell Mol Neurobiol 31:835–846CrossRefGoogle Scholar
  12. De Nardis R, Sattayasai J, Zappia J, Ehrlich D (1988) Neurotoxic effects of kainic acid on developing chick retina. Dev Neurosci 10:256–269CrossRefGoogle Scholar
  13. DeVries SH (2000) Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels. Neuron 28:847–856CrossRefGoogle Scholar
  14. do Nascimento JLM, de Mello FG (1985) Induced release of gamma-aminobutyric acid by a carrier-mediated, high-affinity uptake of l-glutamate in cultured chick retina cells. J Neurochem 45:1820–1827CrossRefGoogle Scholar
  15. Do Nascimento JL, Kubrusly RC, Reis RA, De Mello MC, De Mello FG (1998) Atypical effect of dopamine in modulating the functional inhibition of NMDA receptors of cultured retina cells. Eur J Pharmacol 343:103–110CrossRefGoogle Scholar
  16. Freitas HR, Ferraz G, Ferreira GC, Ribeiro-Resende VT, Chiarini LB, do Nascimento JL, Matos Oliveira KR, Pereira TL, Ferreira LG, Kubrusly RC, Faria RX, Herculano AM, Reis RA (2016) Glutathione-induced calcium shifts in chick retinal glial cells. PLoS ONE 11(4):e0153677CrossRefGoogle Scholar
  17. Gayet-Primo J, Puthussery T (2015) Alterations in kainate receptor and TRPM1 localization in bipolar cells after retinal photoreceptor degeneration. Front Cell Neurosci 9:486CrossRefGoogle Scholar
  18. George A, Schmid KL, Pow DV (2005) Retinal serotonin, eye growth and myopia development in chick. Exp Eye Res 81:616–625CrossRefGoogle Scholar
  19. Gerson SC, Baldessarini RJ (1980) Motor effects of serotonin in the central nervous system. Life Sci 27:1435–1451CrossRefGoogle Scholar
  20. Ghai K, Zelinka C, Fischer AJ (2009) Serotonin released from amacrine neurons is scavenged and degraded in bipolar neurons in the retina. J Neurochem 111:1–14CrossRefGoogle Scholar
  21. Guimaraes-Souza EM, Calaza KC (2012) Selective activation of group III metabotropic glutamate receptor subtypes produces different patterns of gamma-aminobutyric acid immunoreactivity and glutamate release in the retina. J Neurosci Res 90:2349–2361CrossRefGoogle Scholar
  22. Haase J, Killian AM, Magnani F, Williams C (2001) Regulation of the serotonin transporter by interacting proteins. Biochem Soc Trans 29:722–728CrossRefGoogle Scholar
  23. Haj-Dahmane S, Shen RY (2011) Modulation of the serotonin system by endocannabinoid signaling. Neuropharmacology 61:414–420CrossRefGoogle Scholar
  24. Haumann I, Junghans D, Anstotz M, Frotscher M (2017) Presynaptic localization of GluK5 in rod photoreceptors suggests a novel function of high affinity glutamate receptors in the mammalian retina. PLoS ONE 12:e0172967CrossRefGoogle Scholar
  25. Horschitz S, Hummerich R, Schloss P (2001) Structure, function and regulation of the 5-hydroxytryptamine (serotonin) transporter. Biochem Soc Trans 29:728–732CrossRefGoogle Scholar
  26. Huettner JE (2003) Kainate receptors and synaptic transmission. Prog Neurobiol 70:387–407CrossRefGoogle Scholar
  27. Kubrusly RCC, Gunter A, Sampaio L, Martins RS, Schitine CS, Trindade P, Fernandes A, Borelli-Torres R, Miya-Coreixas VS, Rego Costa AC, Freitas HR, Gardino PF, de Mello FG, Calaza KC, Reis RAM (2018) Neuro-glial cannabinoid receptors modulate signaling in the embryonic avian retina. Neurochem Int 112:27–37CrossRefGoogle Scholar
  28. Lima L, Urbina M (1994) Dopamine and serotonin turnover rate in the retina of rabbit, rat, goldfish, and Eugerres plumieri: light effects in goldfish and rat. J Neurosci Res 39:595–603CrossRefGoogle Scholar
  29. Millar TJ, Winder C, Ishimoto I, Morgan IG (1988) Putative serotonergic bipolar and amacrine cells in the chicken retina. Brain Res 439:77–87CrossRefGoogle Scholar
  30. Nakazi M, Bauer U, Nickel T, Kathmann M, Schlicker E (2000) Inhibition of serotonin release in the mouse brain via presynaptic cannabinoid CB1 receptors. Naunyn Schmiedebergs Arch Pharmacol 361:19–24CrossRefGoogle Scholar
  31. Osborne NN (1982) Uptake, localization and release of serotonin in the chick retina. J Physiol 331:469–479CrossRefGoogle Scholar
  32. Osborne NN, Patel S (1984) Postnatal development of serotonin-accumulating neurones in the rabbit retina and an immunohistochemical analysis of the uptake and release of serotonin. Exp Eye Res 38:611–620CrossRefGoogle Scholar
  33. Osborne NN, Nesselhut T, Nicholas DA, Patel S, Cuello AC (1982) Serotonin-containing neurones in vertebrate retinas. J Neurochem 39:1519–1528CrossRefGoogle Scholar
  34. Osborne NN, McCord RJ, Wood J (1995) The effect of kainate on protein kinase C, GABA, and the uptake of serotonin in the rabbit retina in vivo. Neurochem Res 20:635–641CrossRefGoogle Scholar
  35. Puthussery T, Percival KA, Venkataramani S, Gayet-Primo J, Grunert U, Taylor WR (2014) Kainate receptors mediate synaptic input to transient and sustained OFF visual pathways in primate retina. J Neurosci 34:7611–7621CrossRefGoogle Scholar
  36. Rios H, Brusco A, Pecci Saavedra J (1997) Development of serotoninergic chick retinal neurons. Int J Dev Neurosci 15:729–738CrossRefGoogle Scholar
  37. Schutte M, Witkovsky P (1990) Serotonin-like immunoreactivity in the retina of the clawed frog Xenopus laevis. J Neurocytol 19:504–518CrossRefGoogle Scholar
  38. Tao R, Ma Z, Auerbach SB (1996) Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br J Pharmacol 119:1375–1384CrossRefGoogle Scholar
  39. Tao R, Ma Z, Auerbach SB (1997) Influence of AMPA/kainate receptors on extracellular 5-hydroxytryptamine in rat midbrain raphe and forebrain. Br J Pharmacol 121:1707–1715CrossRefGoogle Scholar
  40. Trakhtenberg EF, Pita-Thomas W, Fernandez SG, Patel KH, Venugopalan P, Shechter JM, Morkin MI, Galvao J, Liu X, Dombrowski SM, Goldberg JL (2017) Serotonin receptor 2C regulates neurite growth and is necessary for normal retinal processing of visual information. Dev Neurobiol 77:419–437CrossRefGoogle Scholar
  41. Weiler R, Schutte M (1985) Kainic acid-induced release of serotonin from OFF-bipolar cells in the turtle retina. Brain Res 360:379–383CrossRefGoogle Scholar
  42. Wilhelm M, Zhu B, Gabriel R, Straznicky C (1993) Immunocytochemical identification of serotonin-synthesizing neurons in the vertebrate retina: a comparative study. Exp Eye Res 56:231–240CrossRefGoogle Scholar
  43. Willis GL, Freelance CB (2017) Neurochemical systems of the retina involved in the control of movement. Front Neurol 8:324CrossRefGoogle Scholar
  44. Zahratka JA, Williams PD, Summers PJ, Komuniecki RW, Bamber BA (2015) Serotonin differentially modulates Ca2 + transients and depolarization in a C. elegans nociceptor. J Neurophysiol 113:1041–1050CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Adelaide da Conceição Fonseca Passos
    • 1
  • Anderson Manoel Herculano
    • 1
  • Karen R. H. M. Oliveira
    • 1
  • Silene Maria A. de Lima
    • 2
  • Fernando A. F. Rocha
    • 2
  • Hércules Rezende Freitas
    • 3
    • 4
  • Luzia da Silva Sampaio
    • 3
  • Danniel Pereira Figueiredo
    • 3
  • Karin da Costa Calaza
    • 5
  • Ricardo Augusto de Melo Reis
    • 3
  • José Luiz Martins do Nascimento
    • 1
    Email author
  1. 1.Laboratório de Neuroquímica Molecular e CelularInstituto de Ciências Biológicas, Universidade Federal do Pará, Campus Universitário do GuamáBelém-PABrazil
  2. 2.Lab de NeurobiologiaInstituto de Ciências Biológicas, Universidade Federal do ParáBelém-PABrazil
  3. 3.Laboratório de NeuroquímicaInstituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de JaneiroRio De Janeiro-RJBrazil
  4. 4.Escola de Ciências da Saúde, Centro Universitário IBMRRio De Janeiro-RJBrazil
  5. 5.Lab Neurobiologia da Retina, Programa de Pós-graduação em NeurociênciasUniversidade Federal FluminenseRio De Janeiro-RJBrazil

Personalised recommendations