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Journal of Molecular Neuroscience

, Volume 61, Issue 3, pp 412–422 | Cite as

17β-Estradiol-Induced Synaptic Rearrangements Are Accompanied by Altered Ectonucleotidase Activities in Male Rat Hippocampal Synaptosomes

  • Nataša Mitrović
  • Marina Zarić
  • Dunja Drakulić
  • Jelena Martinović
  • Jean Sévigny
  • Miloš Stanojlović
  • Nadežda Nedeljković
  • Ivana Grković
Article

Abstract

17β-Estradiol (E2) rapidly, by binding to membrane estrogen receptors, activates cell signaling cascades which induce formation of new dendritic spines in the hippocampus of males as in females, but the interaction with other metabolic processes, such as extracellular adenine nucleotides metabolism, are currently unknown. Extracellular adenine nucleotides play significant roles, controlling excitatory glutamatergic synapses and development of neural circuits and synaptic plasticity. Their precise regulation in the synaptic cleft is tightly controlled by ecto-nucleoside triphosphate diphosphohydrolase (NTPDase)/ecto-5′-nucleotidase (eN) enzyme chain. Therefore, we sought to clarify whether a single systemic injection of E2 in male rats is accompanied by changes in the expression of the pre- and postsynaptic proteins and downstream kinases linked to E2-induced synaptic rearrangement as well as alterations in NTPDase/eN pathway in the hippocampal synaptosomes. Obtained data showed activation of mammalian target of rapamycin and upregulation of key synaptic proteins necessary for spine formation, 24 h after systemic E2 administration. In E2-mediated conditions, we found downregulation of NTPDase1 and NTPDase2 and attenuation of adenine nucleotide hydrolysis by NTPDase/eN enzyme chain, without changes in NTPDase3 properties and augmentation of synaptic tissue-nonspecific alkaline phosphatase (TNAP) activity. Despite reduced NTPDase activities, increased TNAP activity probably prevents toxic accumulation of ATP in the extracellular milieu and also hydrolyzes accumulated ADP due to unchanged NTPDase3 activity. Thus, our initial evaluation supports idea of specific roles of different ectonucleotidases and their coordinated actions in E2-mediated spine remodeling and maintenance.

Keywords

17β-estradiol Synaptic proteins Ectonucleotidase Synaptosomes Hippocampus Male rats 

Notes

Acknowledgements

The authors are grateful to Dr. Terence L. Kirley for the generous gift of KLH14 antisera used in the study. We also thank Dr. Anica Horvat for intellectual support and advice. This work was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia, projects Nos. 41014 and 173044. J.S. received support from the Canadian Institutes of Health Research and was also the recipient of a “Chercheur National” Scholarship from the Fonds de Recherche du Québec–Santé.

Author Contributions

IG and NM conceived and designed the experiments. NM, IG, MZ, DD, JM, and MS performed the experiments. IG, NM, and NN analyzed and interpreted data. JS contributed with reagents/materials. IG, NM, and NN wrote the paper. All authors were contributing to the manuscript through critical review and editing and approved the final manuscript.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Belcher SM, Zsarnovszky A, Crawford PA, Hemani H, Spurling L, Kirley TL (2006) Immunolocalization of ecto-nucleoside triphosphate diphosphohydrolase 3 in rat brain: implications for modulation of multiple homeostatic systems including feeding and sleep-wake behaviors. Neuroscience 137:1331–1346CrossRefPubMedGoogle Scholar
  2. Bjelobaba I, Lavrnja I, Parabucki A, Stojkov D, Stojiljkovic M, Pekovic S, Nedeljkovic N (2010) The cortical stab injury induces beading of fibers expressing ecto-nucleoside triphosphate diphosphohydrolase 3. Neuroscience 170:107–116CrossRefPubMedGoogle Scholar
  3. Bonan CD (2012) Ectonucleotidases and nucleotide/nucleoside transporters as pharmacological targets for neurological disorders. CNS Neurol Disord Drug Targets 11:739–750CrossRefPubMedGoogle Scholar
  4. Bonfanti L (2006) PSA-NCAM in mammalian structural plasticity and neurogenesis. Prog Neurobiol 80:129–164CrossRefPubMedGoogle Scholar
  5. Brisevac D, Bjelobaba I, Bajic A, Clarner T, Stojiljkovic M, Beyer C, Andjus P, Kipp M, Nedeljkovic N (2012) Regulation of ecto-5′-nucleotidase (CD73) in cultured cortical astrocytes by different inflammatory factors. Neurochem Int 61:681–688CrossRefPubMedGoogle Scholar
  6. Briz V, Baudry M (2014) Estrogen regulates protein synthesis and actin polymerization in hippocampal neurons through different molecular mechanisms. Front Endocrinol (Lausanne) 5:22Google Scholar
  7. Burnstock G (2007) Physiology and pathophysiology of purinergic neurotransmission. Physiol Rev 87:659–797CrossRefPubMedGoogle Scholar
  8. Corera AT, Doucet G, Fon EA (2009) Long-term potentiation in isolated dendritic spines. PLoS One 4:e6021CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cox ET, Brennaman LH, Gable KL, Hamer RM, Glantz LA, Lamantia AS, Lieberman JA, Gilmore JH, Maness PF, Jarskog LF (2009) Developmental regulation of neural cell adhesion molecule in human prefrontal cortex. Neuroscience 162:96–105CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cunha RA (2001) Regulation of the ecto-nucleotidase pathway in rat hippocampal nerve terminals. Neurochem Res 26:979–991CrossRefPubMedGoogle Scholar
  11. Cunha RA (2005) Neuroprotection by adenosine in the brain: from A(1) receptor activation to A(2A) receptor blockade. Purinergic Signal 1:111–134CrossRefPubMedPubMedCentralGoogle Scholar
  12. Del Puerto A, Wandosell F, Garrido JJ (2013) Neuronal and glial purinergic receptors functions in neuron development and brain disease. Front Cell Neurosci 7:197PubMedPubMedCentralGoogle Scholar
  13. Diez-Zaera M, Diaz-Hernandez JI, Hernandez-Alvarez E, Zimmermann H, Diaz-Hernandez M, Miras-Portugal MT (2011) Tissue-nonspecific alkaline phosphatase promotes axonal growth of hippocampal neurons. Mol Biol Cell 22:1014–1024CrossRefPubMedPubMedCentralGoogle Scholar
  14. Duster R, Prickaerts J, Blokland A (2014) Purinergic signaling and hippocampal long-term potentiation. Curr Neuropharmacol 12:37–43CrossRefPubMedPubMedCentralGoogle Scholar
  15. Fan L, Zhao Z, Orr PT, Chambers CH, Lewis MC, Frick KM (2010) Estradiol-induced object memory consolidation in middle-aged female mice requires dorsal hippocampal extracellular signal-regulated kinase and phosphatidylinositol 3-kinase activation. J Neurosci 30:4390–4400CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fausther M, Lecka J, Soliman E, Kauffenstein G, Pelletier J, Sheung N, Dranoff JA, Sevigny J (2012) Coexpression of ecto-5′-nucleotidase/CD73 with specific NTPDases differentially regulates adenosine formation in the rat liver. Am J Physiol Gastrointest Liver Physiol 302:G447–G459CrossRefPubMedGoogle Scholar
  17. Fortress AM, Fan L, Orr PT, Zhao Z, Frick KM (2013) Estradiol-induced object recognition memory consolidation is dependent on activation of mTOR signaling in the dorsal hippocampus. Learn Mem 20:147–155CrossRefPubMedPubMedCentralGoogle Scholar
  18. Frick KM, Kim J, Tuscher JJ, Fortress AM (2015) Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents. Learn Mem 22:472–493CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gerrow K, Romorini S, Nabi SM, Colicos MA, Sala C, El-Husseini A (2006) A preformed complex of postsynaptic proteins is involved in excitatory synapse development. Neuron 49:547–562CrossRefPubMedGoogle Scholar
  20. Glantz LA, Gilmore JH, Hamer RM, Lieberman JA, Jarskog LF (2007) Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood. Neuroscience 149:582–591CrossRefPubMedPubMedCentralGoogle Scholar
  21. Grkovic I, Bjelobaba I, Nedeljkovic N, Mitrovic N, Drakulic D, Stanojlovic M, Horvat A (2014) Developmental increase in ecto-5′-nucleotidase activity overlaps with appearance of two immunologically distinct enzyme isoforms in rat hippocampal synaptic plasma membranes. J Mol Neurosci 54:109–118CrossRefPubMedGoogle Scholar
  22. Grkovic I, Bjelobaba I, Mitrovic N, Lavrnja I, Drakulic D, Martinovic J, Stanojlovic M, Horvat A, Nedeljkovic N (2016) Expression of ecto-nucleoside triphosphate diphosphohydrolase3 (NTPDase3) in the female rat brain during postnatal development. J Chem Neuroanat 77:10–18CrossRefPubMedGoogle Scholar
  23. Hanics J, Barna J, Xiao J, Millan JL, Fonta C, Negyessy L (2012) Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain. Cell Tissue Res 349:459–471CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hasegawa Y, Hojo Y, Kojima H, Ikeda M, Hotta K, Sato R, Ooishi Y, Yoshiya M, Chung BC, Yamazaki T, Kawato S (2015) Estradiol rapidly modulates synaptic plasticity of hippocampal neurons: involvement of kinase networks. Brain Res 1621:147–161CrossRefPubMedGoogle Scholar
  25. Hoeffer CA, Klann E (2010) mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 33:67–75CrossRefPubMedGoogle Scholar
  26. Hojo Y, Higo S, Ishii H, Ooishi Y, Mukai H, Murakami G, Kominami T, Kimoto T, Honma S, Poirier D, Kawato S (2009) Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus. Endocrinology 150:5106–5112CrossRefPubMedGoogle Scholar
  27. Hojo Y, Munetomo A, Mukai H, Ikeda M, Sato R, Hatanaka Y, Murakami G, Komatsuzaki Y, Kimoto T, Kawato S (2015) Estradiol rapidly modulates spinogenesis in hippocampal dentate gyrus: involvement of kinase networks. Horm Behav 74:149–156CrossRefPubMedGoogle Scholar
  28. Jacome LF, Barateli K, Buitrago D, Lema F, Frankfurt M, Luine VN (2016) Gonadal hormones rapidly enhance spatial memory and increase hippocampal spine density in male rats. Endocrinology 157:1357–1362CrossRefPubMedGoogle Scholar
  29. Kato A, Hojo Y, Higo S, Komatsuzaki Y, Murakami G, Yoshino H, Uebayashi M, Kawato S (2013) Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. Front Neural Circuits 7:149CrossRefPubMedPubMedCentralGoogle Scholar
  30. Kiss DS, Zsarnovszky A, Horvath K, Gyorffy A, Bartha T, Hazai D, Sotonyi P, Somogyi V, Frenyo LV, Diano S (2009) Ecto-nucleoside triphosphate diphosphohydrolase 3 in the ventral and lateral hypothalamic area of female rats: morphological characterization and functional implications. Reprod Biol Endocrinol 7:31CrossRefPubMedPubMedCentralGoogle Scholar
  31. Koles L, Kato E, Hanuska A, Zadori ZS, Al-Khrasani M, Zelles T, Rubini P, Illes P (2016) Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems. Purinergic Signal 12:1–24CrossRefPubMedGoogle Scholar
  32. Kukulski F, Komoszynski M (2003) Purification and characterization of NTPDase1 (ecto-apyrase) and NTPDase2 (ecto-ATPase) from porcine brain cortex synaptosomes. Eur J Biochem 270:3447–3454CrossRefPubMedGoogle Scholar
  33. Kukulski F, Levesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, Robson SC, Kirley TL, Sevigny J (2005) Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal 1:193–204CrossRefPubMedPubMedCentralGoogle Scholar
  34. Kulkarni J, Gavrilidis E, Worsley R, Van Rheenen T, Hayes E (2013) The role of estrogen in the treatment of men with schizophrenia. Int J Endocrinol Metab 11:129–136CrossRefPubMedPubMedCentralGoogle Scholar
  35. Langer D, Hammer K, Koszalka P, Schrader J, Robson S, Zimmermann H (2008) Distribution of ectonucleotidases in the rodent brain revisited. Cell Tissue Res 334:199–217CrossRefPubMedGoogle Scholar
  36. Leranth C, Petnehazy O, MacLusky NJ (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23:1588–1592PubMedGoogle Scholar
  37. Luine VN, Frankfurt M (2012) Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density. Front Neuroendocrinol 33:388–402CrossRefPubMedPubMedCentralGoogle Scholar
  38. Millan JL (2006) Alkaline phosphatases : structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic Signal 2:335–341CrossRefPubMedPubMedCentralGoogle Scholar
  39. Mitrovic N, Gusevac I, Drakulic D, Stanojlovic M, Zlatkovic J, Sevigny J, Horvat A, Nedeljkovic N, Grkovic I (2016a) Regional and sex-related differences in modulating effects of female sex steroids on ecto-5′-nucleotidase expression in the rat cerebral cortex and hippocampus. Gen Comp Endocrinol 235:100–107CrossRefPubMedGoogle Scholar
  40. Mitrovic N, Zaric M, Drakulic D, Martinovic J, Stanojlovic M, Sevigny J, Horvat A, Nedeljkovic N, Grkovic I (2016b) 17beta-estradiol upregulates ecto-5′-nucleotidase (CD73) in hippocampal synaptosomes of female rats through action mediated by estrogen receptor-alpha and -beta. Neuroscience 324:286–296CrossRefPubMedGoogle Scholar
  41. Mukai H, Tsurugizawa T, Murakami G, Kominami S, Ishii H, Ogiue-Ikeda M, Takata N, Tanabe N, Furukawa A, Hojo Y, Ooishi Y, Morrison JH, Janssen WG, Rose JA, Chambon P, Kato S, Izumi S, Yamazaki T, Kimoto T, Kawato S (2007) Rapid modulation of long-term depression and spinogenesis via synaptic estrogen receptors in hippocampal principal neurons. J Neurochem 100:950–967CrossRefPubMedGoogle Scholar
  42. Murakami G, Hojo Y, Ogiue-Ikeda M, Mukai H, Chambon P, Nakajima K, Ooishi Y, Kimoto T, Kawato S (2015) Estrogen receptor KO mice study on rapid modulation of spines and long-term depression in the hippocampus. Brain Res 1621:133–146CrossRefPubMedGoogle Scholar
  43. Obradovic M, Stewart AJ, Pitt SJ, Labudovic-Borovic M, Sudar E, Petrovic V, Zafirovic S, Maravic-Stojkovic V, Vasic V, Isenovic ER (2014) In vivo effects of 17beta-estradiol on cardiac Na(+)/K(+)-ATPase expression and activity in rat heart. Mol Cell Endocrinol 388:58–68CrossRefPubMedGoogle Scholar
  44. Phan A, Suschkov S, Molinaro L, Reynolds K, Lymer JM, Bailey CD, Kow LM, MacLusky NJ, Pfaff DW, Choleris E (2015) Rapid increases in immature synapses parallel estrogen-induced hippocampal learning enhancements. Proc Natl Acad Sci U S A 112:16018–16023CrossRefPubMedPubMedCentralGoogle Scholar
  45. Potier M, Georges F, Brayda-Bruno L, Ladepeche L, Lamothe V, Al Abed AS, Groc L, Marighetto A (2016) Temporal memory and its enhancement by estradiol requires surface dynamics of hippocampal CA1 N-methyl-D-aspartate receptors. Biol Psychiatry 79:735–745CrossRefPubMedGoogle Scholar
  46. Rebola N, Lujan R, Cunha RA, Mulle C (2008) Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses. Neuron 57:121–134CrossRefPubMedGoogle Scholar
  47. Robson SC, Sevigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal 2:409–430CrossRefPubMedPubMedCentralGoogle Scholar
  48. Sebastian-Serrano A, de Diego-Garcia L, Martinez-Frailes C, Avila J, Zimmermann H, Millan JL, Miras-Portugal MT, Diaz-Hernandez M (2015) Tissue-nonspecific alkaline phosphatase regulates purinergic transmission in the central nervous system during development and disease. Comput Struct Biotechnol J 13:95–100CrossRefPubMedGoogle Scholar
  49. Sebastiao AM, Ribeiro JA (2015) Neuromodulation and metamodulation by adenosine: impact and subtleties upon synaptic plasticity regulation. Brain Res 1621:102–113CrossRefPubMedGoogle Scholar
  50. Sellers K, Raval P, Srivastava DP (2015a) Molecular signature of rapid estrogen regulation of synaptic connectivity and cognition. Front Neuroendocrinol 36:72–89CrossRefPubMedGoogle Scholar
  51. Sellers KJ, Erli F, Raval P, Watson IA, Chen D, Srivastava DP (2015b) Rapid modulation of synaptogenesis and spinogenesis by 17beta-estradiol in primary cortical neurons. Front Cell Neurosci 9:137CrossRefPubMedPubMedCentralGoogle Scholar
  52. Sevigny J, Sundberg C, Braun N, Guckelberger O, Csizmadia E, Qawi I, Imai M, Zimmermann H, Robson SC (2002) Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation. Blood 99:2801–2809CrossRefPubMedGoogle Scholar
  53. Sheng M, Kim E (2011) The postsynaptic organization of synapses. Cold Spring Harb Perspect Biol 3. doi: 10.1101/cshperspect.a005678
  54. Smith CC, Vedder LC, McMahon LL (2009) Estradiol and the relationship between dendritic spines, NR2B containing NMDA receptors, and the magnitude of long-term potentiation at hippocampal CA3-CA1 synapses. Psychoneuroendocrinology 34(Suppl 1):S130–S142CrossRefPubMedGoogle Scholar
  55. Srivastava DP, Woolfrey KM, Jones KA, Shum CY, Lash LL, Swanson GT, Penzes P (2008) Rapid enhancement of two-step wiring plasticity by estrogen and NMDA receptor activity. Proc Natl Acad Sci U S A 105:14650–14655CrossRefPubMedPubMedCentralGoogle Scholar
  56. Srivastava DP, Woolfrey KM, Penzes P (2013) Insights into rapid modulation of neuroplasticity by brain estrogens. Pharmacol Rev 65:1318–1350CrossRefPubMedPubMedCentralGoogle Scholar
  57. Stanojevic I, Bjelobaba I, Nedeljkovic N, Drakulic D, Petrovic S, Stojiljkovic M, Horvat A (2011) Ontogenetic profile of ecto-5′-nucleotidase in rat brain synaptic plasma membranes. Int J Dev Neurosci 29:397–403CrossRefPubMedGoogle Scholar
  58. Stanojlovic M, Zlatkovic J, Gusevac I, Grkovic I, Mitrovic N, Zaric M, Horvat A, Drakulic D (2015) Repeated low-dose 17beta-estradiol treatment prevents activation of apoptotic signaling both in the synaptosomal and cellular fraction in rat prefrontal cortex following cerebral ischemia. Neurochem Int 83-84:1–8CrossRefPubMedGoogle Scholar
  59. Stanojlovic M, Gusevac I, Grkovic I, Mitrovic N, Zlatkovic J, Horvat A, Drakulic D (2016) Repeated estradiol treatment attenuates chronic cerebral Hypoperfusion-induced neurodegeneration in rat hippocampus. Cell Mol Neurobiol 36:989–999CrossRefPubMedGoogle Scholar
  60. Sudhof TC (1995) The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature 375:645–653CrossRefPubMedGoogle Scholar
  61. Tan O, Fadiel A, Chang A, Demir N, Jeffrey R, Horvath T, Garcia-Segura LM, Naftolin F (2009) Estrogens regulate posttranslational modification of neural cell adhesion molecule during the estrogen-induced gonadotropin surge. Endocrinology 150:2783–2790CrossRefPubMedGoogle Scholar
  62. Tuscher JJ, Luine V, Frankfurt M, Frick KM (2016) Estradiol-mediated spine changes in the dorsal hippocampus and medial prefrontal cortex of ovariectomized female mice depend on ERK and mTOR activation in the dorsal hippocampus. J Neurosci 36:1483–1489CrossRefPubMedPubMedCentralGoogle Scholar
  63. Vorhoff T, Zimmermann H, Pelletier J, Sevigny J, Braun N (2005) Cloning and characterization of the ecto-nucleotidase NTPDase3 from rat brain: predicted secondary structure and relation to other members of the E-NTPDase family and actin. Purinergic Signal 1:259–270CrossRefPubMedPubMedCentralGoogle Scholar
  64. Woolley CS, McEwen BS (1993) Roles of estradiol and progesterone in regulation of hippocampal dendritic spine density during the estrous cycle in the rat. J Comp Neurol 336:293–306CrossRefPubMedGoogle Scholar
  65. Zimmermann H, Zebisch M, Strater N (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 8:437–502CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Nataša Mitrović
    • 1
  • Marina Zarić
    • 1
  • Dunja Drakulić
    • 1
  • Jelena Martinović
    • 1
  • Jean Sévigny
    • 2
    • 3
  • Miloš Stanojlović
    • 1
  • Nadežda Nedeljković
    • 4
  • Ivana Grković
    • 1
  1. 1.Department of Molecular Biology and Endocrinology, VINČA Institute of Nuclear SciencesUniversity of BelgradeBelgradeSerbia
  2. 2.Département de microbiologie-infectiologie et d’immunologie, Faculté de MédecineUniversité LavalQuébecCanada
  3. 3.Centre de recherche du CHU de QuébecUniversité LavalQuébecCanada
  4. 4.Institute for Physiology and Biochemistry, Faculty of BiologyUniversity of BelgradeBelgradeSerbia

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