Alterations in the threshold of the potassium concentration to evoke cortical spreading depression during the natural estrous cycle in mice

Highlights

• This study explored the inducibility of CSD in the natural estrous cycle of mice.

• Susceptibility to the development of CSD is elevated in the diestrus phase.

• Serum estrogen is significantly higher in diestrus compared to estrus.

• The estrogen receptor antagonist decreased the susceptibility to CSD.

• Neuronal excitability relevant to CSD differs among the natural estrous cycle.

Abstract

Cortical spreading depression (CSD) has been implicated in a variety of neurological disorders. However, the relationship between serum sex hormones and susceptibility to the development of CSD in naturally estrous cycling female animals is largely unknown. The natural estrous cycle of mice consists of four stages, namely, proestrus, estrus, metestrus and diestrus. We measured the serum concentration of estradiol and progesterone in estrus and diestrus and compared the minimum potassium concentrations necessary to evoke CSD in each stage and in males. In diestrus, the minimum potassium concentration required to evoke CSD was significantly lower compared to the other three phases and male animals. The serum level of estradiol is significantly higher and serum level of progesterone is significantly lower in diestrus compared to estrus. Furthermore, when we administered an estrogen receptor antagonist, the susceptibility to the development of CSD was decreased. Conversely, the administration of a progesterone receptor antagonist increased the susceptibility to CSD. Our results demonstrated that neuronal excitability related to CSD induction differs among the natural estrous phases 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.