Spatial and temporal changes in the PGE2 EP2 receptor in mice hippocampi during postnatal development and its relationship with cyclooxygenase-2

Document Type : Original Article

Authors

1 Department of Veterinary Medicine & Institute of Veterinary Science, Chungnam National University, Daejeon 34134, South Korea

2 Department of Anatomy, College of Veterinary Medicine, and Veterinary Science Research Institute, Konkuk University, Seoul 05030, South Korea

3 Department of Anatomy and Cell Biology, College of Veterinary Medicine, and Research Institute for Veterinary Science, Seoul National University, Seoul 08826, South Korea

4 Department of Anatomy, School of Medicine, Wonkwang University, Iksan 54538, South Korea

5 Department of Biomedical Laboratory Science, College of Medical Sciences, Soonchunhyang University, Asan 31538, South Korea

6 Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung 25457, South Korea

7 Department of Anatomy, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, South Korea

Abstract

Objective(s): Prostaglandin E2 E-prostanoid 2 receptor (PGE2 EP2), downstream of cyclooxygenase-2 (COX-2), plays an important role in inflammatory responses, but there are some reports about synaptic functions of COX-2 and PGE2 EP2 in the hippocampus.
Materials and Methods: C57BL/6J mice were sacrificed at postnatal days (P) 1, 7, 14, 28, and 56 for immunohistochemical staining for EP2 and doublecortin as well as western blot for EP2. In addition, COX-2 knockout and its wild-type mice were euthanized for immunohistochemical staining for EP2.
Results: EP2 immunoreactivity was observed in the majority of the cells in the dentate gyrus at P1 and P7, while at P14, it was detected in the outer granule cell layer and was confined to its subgranular zone at P28 and P56. EP2 protein levels in the hippocampal homogenates were also highest at P7 and lowest at P56. EP2 immunoreactivity was partially colocalized, with doublecortin (DCX)-immunoreactive neuroblasts appearing in the mid-zone of the granule cell layer at P14 and in the subgranular zone of the dentate gyrus at P28. Co-localization of EP2 and DCX was significantly decreased in the dentate gyrus in the P28 group compared with that in the P14 group. In COX-2 knockout mice, EP2 immunoreactivity was significantly decreased in the hippocampal CA1 region (P=0.000165) and dentate gyrus (P=0.00898).
Conclusion: EP2 decreases with age, which is expressed in DCX-immunoreactive neuroblasts in the dentate gyrus. This suggests that EP2 is closely linked to structural lamination and adult neurogenesis in the dentate gyrus.

Keywords

References

1. Hevner RF. Evolution of the mammalian dentate gyrus. J Comp Neurol 2016; 524:578-594.
2. Avchalumov Y, Mandyam CD. Plasticity in the hippocampus, neurogenesis and drugs of abuse. Brain Sci 2021; 11:404-418.
4. Bayer SA. Development of the hippocampal region in the rat. II. Morphogenesis during embryonic and early postnatal life. J Comp Neurol 1980; 190:115-134.
5. Toda T, Gage FH. Review: Adult neurogenesis contributes to hippocampal plasticity. Cell Tissue Res 2018; 373:693-709.
6. Yang CH, Di Antonio A, Kirschen GW, Varma P, Hsieh J, Ge S. Circuit integration initiation of new hippocampal neurons in the adult brain. Cell Rep 2020; 30:959-968.e3.
7. Yoo DY, Yoo KY, Choi JW, Kim W, Lee CH, Choi JH, et al. Time course of postnatal distribution of doublecortin immunoreactive developing/maturing neurons in the somatosensory cortex and hippocampal CA1 region of C57BL/6 mice. Cell Mol Neurobiol 2011; 31:729-736.
8. Famitafreshi H, Karimian M. Prostaglandins as the agents that modulate the course of brain disorders. Degener Neurol Neuromuscul Dis 2020; 10:1-13.
9. López DE, Ballaz SJ. The role of brain cyclooxygenase-2 (Cox-2) beyond neuroinflammation: Neuronal homeostasis in memory and anxiety. Mol Neurobiol 2020; 57: 5167-5176.
10. Yagami T, Koma H, Yamamoto Y. Pathophysiological roles of cyclooxygenases and prostaglandins in the central nervous system. Mol Neurobiol 2016; 53:4754-4771.
11. Shrestha S, Kim MJ, Eldridge M, Lehmann ML, Frankland M, Liow JS, et al. PET measurement of cyclooxygenase-2 using a novel radioligand: upregulation in primate neuroinflammation and first-in-human study. J Neuroinflammation 2020; 17:140-156.
12. Lee CH, Yoo KY, Choi JH, Park OK, Hwang IK, Kang IJ, et al. Cyclooxygenase-2 immunoreactivity and protein level in the gerbil hippocampus during normal aging. Neurochem Res 2010; 35:99-106.
13. Jung HY, Yoo DY, Kim JW, Kwon HJ, Lee KY, Choi JH, et al. Age-associated alterations in constitutively expressed cyclooxygenase-2 immunoreactivity and protein levels in the hippocampus. Mol Med Rep 2017; 15:4333-4337.
14. Jung HY, Yoo DY, Nam SM, Kim JW, Kim W, Kwon HJ, et al. Postnatal changes in constitutive cyclooxygenase2 expression in the mice hippocampus and its function in synaptic plasticity. Mol Med Rep 2019; 19:1996-2004.
15. Goncalves MB, Williams EJ, Yip P, Yáñez-Muñoz RJ, Williams G, Doherty P. The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain. Br J Pharmacol 2010; 159:1118-1125.
16. Nam SM, Kim JW, Yoo DY, Choi JH, Kim W, Jung HY, et al. Comparison of pharmacological and genetic inhibition of cyclooxygenase-2: effects on adult neurogenesis in the hippocampal dentate gyrus. J Vet Sci 2015; 16:245-251.
17. Kim GH, Lim K, Yang HS, Lee JK, Kim Y, Park SK, et al. Improvement in neurogenesis and memory function by administration of Passiflora incarnata L. extract applied to sleep disorder in rodent models. J Chem Neuroanat 2019; 98:27-40.
18. Cowley TR, Fahey B, O’Mara SM. COX-2, but not COX-1, activity is necessary for the induction of perforant path long-term potentiation and spatial learning in vivo. Eur J Neurosci 2008; 27:2999-3008.
19. Sang N, Zhang J, Marcheselli V, Bazan NG, Chen C. Postsynaptically synthesized prostaglandin E2 (PGE2) modulates hippocampal synaptic transmission via a presynaptic PGE2 EP2 receptor. J Neurosci 2005; 25:9858-9870.
20. Uchida K, Kumihashi K, Kurosawa S, Kobayashi T, Itoi K, Machida T. Stimulatory effects of prostaglandin E2 on neurogenesis in the dentate gyrus of the adult rat. Zoolog Sci 2002; 19:1211-1216.
21. Sugimoto Y, Narumiya S. Prostaglandin E receptors. J Biol Chem 2007; 282:11613-11617.
22. McCullough L, Wu L, Haughey N, Liang X, Hand T, Wang Q, Breyer RM, Andreasson K. Neuroprotective function of the PGE2 EP2 receptor in cerebral ischemia. J Neurosci 2004; 24:257-268.
23. Ma Y, Matsuwaki T, Yamanouchi K, Nishihara M. Glucocorticoids suppress the protective effect of cyclooxygenase-2-related signaling on hippocampal neurogenesis under acute immune stress. Mol Neurobiol 2017; 54:1953-1966.
24. Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 1996; 16:2027-2033.
25. Hwang IK, Yoo KY, Li H, Choi JH, Kwon YG, Ahn Y, et al. Differences in doublecortin immunoreactivity and protein levels in the hippocampal dentate gyrus between adult and aged dogs. Neurochem Res 2007; 32:1604-1609.
26. Hwang IK, Yoo KY, Yi SS, Kwon YG, Ahn YK, Seong JK,             et al. Age-related differentiation in newly generated DCX immunoreactive neurons in the subgranular zone of the gerbil dentate gyrus. Neurochem Res 2008; 33:867-872.
27. Bettio LEB, Rajendran L, Gil-Mohapel J. The effects of aging in the hippocampus and cognitive decline. Neurosci Biobehav Rev 2017; 79:66-86.
28. Chen C, Magee JC, Bazan NG. Cyclooxygenase-2 regulates prostaglandin E2 signaling in hippocampal long-term synaptic plasticity. J Neurophysiol 2002; 87:2851-2857.
29. Shaw KN, Commins S, O’Mara SM. Deficits in spatial learning and synaptic plasticity induced by the rapid and competitive broad-spectrum cyclooxygenase inhibitor ibuprofen are reversed by increasing endogenous brain-derived neurotrophic factor. Eur J Neurosci 2003; 17:2438-2446.
30. Savonenko A, Munoz P, Melnikova T, Wang Q, Liang X, Breyer RM, et al. Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor. Exp Neurol 2009; 217:63-73.
31. Yang H, Zhang J, Breyer RM, Chen C. Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor. J Neurochem 2009; 108:295-304.
32. Aoki T, Nishimura M, Matsuoka T, Yamamoto K, Furuyashiki T, Kataoka H, et al. PGE2-EP2 signalling in endothelium is activated by haemodynamic stress and induces cerebral aneurysm through an amplifying loop via NF-κB. Br J Pharmacol 2011; 163:1237-1249.
33. Sonoshita M, Takaku K, Sasaki N, Sugimoto Y, Ushikubi F, Narumiya S, et al. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in ApcΔ716 knockout mice. Nat Med 2001; 7:1048-1051.
34. Hiruma H, Ichikawa T, Kobayashi H, Hoka S, Takenaka T, Kawakami T. Prostaglandin E2 enhances axonal transport and neuritogenesis in cultured mouse dorsal root ganglion neurons. Neuroscience 2000; 100:885-891.
35. Mitani K, Sekiguchi F, Maeda T, Tanaka Y, Yoshida S, Kawabata A. The prostaglandin E2/EP4 receptor/cyclic AMP/T-type Ca2+ channel pathway mediates neuritogenesis in sensory neuron-like ND7/23 cells. J Pharmacol Sci 2016; 130:177-180.
36. Anglada-Huguet M, Vidal-Sancho L, Giralt A, García-Díaz Barriga G, Xifró X, Alberch J. Prostaglandin E2 EP2 activation reduces memory decline in R6/1 mouse model of Huntington’s disease by the induction of BDNF-dependent synaptic plasticity. Neurobiol Dis 2016; 95:22-34.
37. Regan JW. EP2 and EP4 prostanoid receptor signaling. Life Sci 2003; 74:143-153.
38. Hwang IK, Yoo KY, Yoo DY, Choi JW, Lee CH, Choi JH, et al. Time-course of changes in phosphorylated CREB in neuroblasts and BDNF in the mouse dentate gyrus at early postnatal stages. Cell Mol Neurobiol 2011; 31:669-674.
Iranian Journal of Basic Medical Sciences
Volume 24, Issue 7
July 2021
Pages 908-913

Files

Share

How to cite

Statistics