Alterations in the threshold of the potassium concentration to evoke cortical spreading depression during the natural estrous cycle in mice
Introduction
The phenomenon of cortical spreading depression (CSD) was initially reported by Leão as a reversible response of the rabbit cerebral cortex that manifested itself as the near-complete depolarization of neurons and glial cells, followed by sustained suppression of spontaneous neuronal activity (Leão, 1944). CSD is provoked by electrical, mechanical or chemical stimulation with potassium to a point of the cortical tissue in various animals. CSD is known to spread through the cortical tissue from the initiation site at a rate of 2–5 mm/min, with the deflection of DC potential and subsequent suppression of electroencephalogram activity (Ayata and Lauritzen, 2015). CSD research in animal models has provided important information about its pathophysiological role in many neurological disorders, including migraine and stroke (Bolay et al., 2002, Dreier, 2011, Iwashita et al., 2013, Moskowitz et al., 2004, Sukhotinsky et al., 2010, Toriumi et al., 2016).
Migraine headaches are known to predominantly affect women; their prevalence in women is approximately three times higher than that in men (Lipton et al., 2002, Sakai and Igarashi, 1997). The precise mechanism underlying migraines has not been established, but CSD is thought to have a fundamental role in migraines, especially in the development of the aura that accompanies a migraine (Hadjikhani et al., 2001, Hauge et al., 2009, Moskowitz et al., 2004).
In addition to neuronal activity related to the estrus cycles observed in seizure or hypoxic tolerance (Kasischke et al., 1999, Scharfman and MacLusky, 2006), much attention has been focused on the relationship between CSD and sex steroid hormones, such as estrogen and progesterone, because of the epidemiological predominance of women among migraine sufferers (Bolay et al., 2011, Brennan et al., 2007, Eikermann-Haerter et al., 2009, Guedes et al., 2009, Sachs et al., 2007). However, most studies exploring this relationship have been conducted in experimental settings involving ovariectomy or the exogenous administration of female sex steroids, and there is little data on alterations in the susceptibility to the development of CSD with regard to the natural estrous cycle. In the present study, we examined the threshold for evoking CSD after determining the stage of the female estrous cycle in mice. We obtained in vivo evidence that the susceptibility to the development of CSD differs during the stages of the natural estrous cycle in mice.
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Animals
Animals were used with the approval (No. 09058) of the Animal Ethics Committee of Keio University (Tokyo, Japan), and all experimental procedures were in accordance with the university's guidelines and the ARRIVE (animal research: reporting in vivo experiments) reporting guidelines for the care and use of laboratory animals. All of the procedures were undertaken with utmost caution to minimize the suffering of the animals. To maintain the regularity of the natural estrous cycle, the animals
Minimum potassium concentrations that evoked CSD
The application of KCl induced negative deflections of the DC potential (i.e., CSD). Fig. 2 shows representative data of the minimum potassium concentrations that evoked CSD in each stage of the estrous cycle and in males. As shown in Fig. 3, the minimum potassium concentrations that evoked CSD were 0.21 ± 0.04 M in the proestrus stage, 0.26 ± 0.04 M in the estrus stage, 0.21 ± 0.04 M in the metestrus stage, 0.12 ± 0.04 M in the diestrus stage and 0.23 ± 0.05 M in males. In the diestrus stage, the minimal
Discussion
The results of our study demonstrated a significant alteration in the threshold to evoke CSD during the natural estrous cycle in mice. We observed that the diestrus stage exhibited the lowest threshold and the estrus stage the highest threshold. In addition, the serum level of estradiol was significantly higher in the diestrus than in the estrus stage, and the serum level of progesterone was significantly higher in the estrus than in the diestrus stage.
In mice, it was reported that increased
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This research was supported in part by a Health Labor Sciences Research Grant (Research on Region Medical to N. Suzuki; H24-Iryo-Ippan-023) from the Ministry of Health, Labor and Welfare of Japan and in part by Grant-in-Aid for Scientific Research (C) (grant number 16K08996 to T. Shimizu) from Japan Society for the Promotion of Science (JSPS).
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