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Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement

Abstract

Purinergic signaling is the main synaptic and non-synaptic signaling system in brain. ATP acts as a fast excitatory transmitter, while adenosine sets a global inhibitory tone within hippocampal neuronal networks. ATP and adenosine are interconnected by ectonucleotidase enzymes, which convert ATP to adenosine. Existing data point to the converging roles of ovarian steroids and purinergic signaling in synapse formation and refinement and synapse activity in the hippocampus. Therefore, in the present study, we have used enzyme histochemistry and expression analysis to obtain data on spatial distribution and expression of ecto-enzymes NTPDase1, NTPDase2, and ecto-5′-nucleotidase (eN) after removal of ovaries (OVX) and estradiol replacement (E2) in female rat hippocampus. The results show that target ectonucleotidases are predominantly localized in synapse-rich hippocampal layers. The most represented NTPDase in the hippocampal tissue is NTPDase2, being at the same time the mostly affected ectonucleotidase by OVX and E2. Specifically, OVX decreases the expression of NTPDase2 and eN, whereas E2 restores their expression to control level. Impact of OVX and E2 on ectonucleotidase expression was also examined in purified synaptosome (SYN) and gliosome (GLIO) fractions. Data reveal that SYN expresses NTPDase1 and NTPDase2, both of which are reduced following OVX and restored with E2. GLIO exhibits NTPDase2-mediated ATP hydrolysis, which falls in OVX, and recovers by E2. These changes in the activity occur without parallel changes in NTPDase2-protein abundance. The same holds for eN. The lack of correlation between NTPDase2 and eN activities and their respective protein abundances suggest a non-genomic mode of E2 action, which is studied further in primary astrocyte culture. Since ovarian steroids shape hippocampal synaptic networks and regulate ectonucleotidase activities, it is possible that cognitive deficits seen after ovary removal may arise from the loss of E2 modulatory actions on ectonucleotidase expression in the hippocampus.

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Acknowledgements

The authors thank Dr. Terence Kirley from the University of Cincinnati, OH, USA, for a kind gift of rabbit anti-rat NTPDase2 and NTPDase3 antibodies used in this study.

Funding

The study was entirely supported by Ministry of Education, Science and Technological Development of the Republic of Serbia Nos. OI173044 and III41014.

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Correspondence to Ivana Grković.

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All experimental procedures involving rats were approved by the Ethical Committee for the Use of Laboratory Animals of Vinča Institute of Nuclear Sciences, Belgrade, Republic of Serbia (Application No. 02/11) and carried out according to the European Communities Council Directive (2010/63/EU).

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The authors declare that they have no conflict of interest.

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Supplementary Figure 1

Microglial cells in the stratum oriens, labeled with ATP enzyme histochemistry. (A) In control animals (Int), microglial cells exhibit typical small ovoid cell body with radially oriented ramified processes. (B) Removal of ovaries (OVX) induced visible changes the morphology of microglia, which became slightly enlarged and with a bipolar, lengthwise orientation of processes giving them the appearance of a less ramified cells. (C) Treatment with E2 restored highly ramified appearance similar to that found in control. Scale bar: 20 μm (PNG 1707 kb)

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Grković, I., Mitrović, N., Dragić, M. et al. Spatial Distribution and Expression of Ectonucleotidases in Rat Hippocampus After Removal of Ovaries and Estradiol Replacement. Mol Neurobiol 56, 1933–1945 (2019). https://doi.org/10.1007/s12035-018-1217-3

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Keywords

  • Ectonucleotidases
  • Hippocampus
  • Ovariectomy
  • Estradiol
  • Astrocytes