Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy

Abstract

In catamenial epilepsy, seizures exhibit a cyclic pattern that parallels the menstrual cycle. Many studies suggest that catamenial seizures are caused by fluctuations in gonadal hormones during the menstrual cycle, but this has been difficult to study in rodent models of epilepsy because the ovarian cycle in rodents, called the estrous cycle, is disrupted by severe seizures. Thus, when epilepsy is severe, estrous cycles become irregular or stop. Therefore, we modified kainic acid (KA)- and pilocarpine-induced status epilepticus (SE) models of epilepsy so that seizures were rare for the first months after SE, and conducted video-EEG during this time. The results showed that interictal spikes (IIS) occurred intermittently. All rats with regular 4-day estrous cycles had IIS that waxed and waned with the estrous cycle. The association between the estrous cycle and IIS was strong: if the estrous cycles became irregular transiently, IIS frequency also became irregular, and when the estrous cycle resumed its 4-day pattern, IIS frequency did also. Furthermore, when rats were ovariectomized, or males were recorded, IIS frequency did not show a 4-day pattern. Systemic administration of an estrogen receptor antagonist stopped the estrous cycle transiently, accompanied by transient irregularity of the IIS pattern. Eventually all animals developed severe, frequent seizures and at that time both the estrous cycle and the IIS became irregular. We conclude that the estrous cycle entrains IIS in the modified KA and pilocarpine SE models of epilepsy. The data suggest that the ovarian cycle influences more aspects of epilepsy than seizure susceptibility.

Increased gyrification and aberrant adult neurogenesis of the dentate gyrus in adult rats

“…To determine the time-dependence of gyrification, additional pilocarpine-treated animals were euthanized 1–3 days ( n = 5), 7–8 days ( n = 5) or 14–17 days ( n = 5) after SE. To determine if the effects of SE in male rats were similar in females, KA was used because it elicits SE reliably in males and females but pilocarpine often fails to elicit SE in females (Scharfman and MacLusky 2014; D’Amour et al 2015). For these experiments, five male rats and six female rats were injected with KA, had SE, and were euthanized >1 month later.…”

“…The first eight females that were used did not have SE after 380 mg/kg of pilocarpine and another eight did not have SE when the dose was 400 mg/kg, which we reported before (Scharfman and MacLusky 2014; D’Amour et al 2015), so KA was used (see below).…”

“…KA (12 mg/kg; Milestone Pharmatech USA Inc.) was injected in male and female rats at the same ages as those used for pilocarpine, with methods described elsewhere (Scharfman and MacLusky 2014; D’Amour et al 2015). All males and females exhibited SE in response to KA ( n = 5 and 6, respectively).…”

PTEN deletion increases hippocampal granule cell excitability in male and female mice

“…Although no differences in field potential responses were found between males and females in the present study, and gross differences in seizure phenotype were not evident in past work with this model (Pun et al, 2012), future studies – categorizing females by the estrous phase – could reveal differences. Interictal spike frequency, for example, has been shown to vary with the estrous cycle phase in the kainic acid model of epilepsy (D’Amour et al, 2015), and this is therefore a promising target.…”

Glial source of nitric oxide in epileptogenesis: A target for disease modification in epilepsy

“…Estradiol peaks at midcycle and progesterone declines before menstruation begins (Backstrom et al, 2003; Herzog and Frye, 2003; Herzog et al, 2004 and 2011). These alterations influence the receptor plasticity in the brain, and cause premenstrual syndrome, migraine and “catamenial” epilepsy in humans (Backstrom et al, 2003; Herzog et al, 2011; Amour et al, 2015). Low progesterone levels during perimenstrual or before ovulation trigger frequent seizures and they could become refractory to the conventional AEDs (Herzog and Frye, 2003; Herzog et al, 2004).…”