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


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.


17β-estradiol Synaptic proteins Ectonucleotidase Synaptosomes Hippocampus Male rats 



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.


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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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