Abstracts

Rationale: Catamenial epilepsy, a phenomena in which seizures cluster around specific phases of the menstrual cycle, has been shown to occur in about 30% of women with epilepsy (Joshi and Kapur, 2019). This phenomena has been linked to fluctuations in hormone levels including estrogen and progesterone, which have pro- and anti-seizure effects respectively (Carver et al., 2014; Tada et al., 2015). In addition, cyclic multidien variation in interictal epileptiform discharge (IEA) and seizure risk has been identified in humans and rodents (Baud et al., 2018, 2019). In a large study using the chronically implanted NeuroPace device in humans, most of the subjects exhibited a 26-30 day periodicity in IEA rates, however, distributions were similar for both sexes (Baud et al., 2018). It is not clear, therefore, how and if circadian and multidien fluctuations in excitability interact with the hormonal fluctuations to modulate seizure risk and how these relationships might differ between the sexes. Using optogenetic population discharge thresholds we explore the relationship between instantaneous network excitability and the estrous cycle in female mice.

Methods: Female mice were chronically implanted with a satellite array consisting of individually placed microwires in hippocampal and peri-hippocampal structures. Optogenetic population discharge thresholds to track network excitability over time as previously described (Klorig et al., 2019). Optogenetic light-intensity response curves (20 levels, 5s ISI) were used to track network excitability over a 4-hour period, twice weekly for >100 days. Behavioral state (wake, NREM, REM) was quantified from inter-stimulus periods using a convolutional neural network–based automated sleep scoring system. The phase of the estrous cycle for each recording was determined via vaginal cytology.

Results: Long-term oPDT recordings support a modest effect of estrus cycle phase on network excitability with proestrus being more excitable than estrus or diestrus suggesting the oPDT is sensitive to estrogen levels (p = 0.0103). There was no detectable difference between estrus and diestus suggesting the oPDT is insensitive to changing progesterone levels. Although network excitability was strongly modulated by sleep state, there was no correlation between estrous cycle and behavioral state duration.

Conclusions: Using long-term chronic recordings we show that network excitability was higher (lower population discharge threshold) during proestrus as compared to estrus or diestrus.

Funding: Please list any funding that was received in support of this abstract.: AES JIRA; NINDS R21 NS116519-01A1.