Seizure burden fluctuates with the female reproductive cycle in a mouse model of chronic temporal lobe epilepsy

Jiang, Li; Leverton, Leanna K.; Naganatanahalli, Laxmi Manisha; Christian‐Hinman, Catherine A.

doi:10.1016/j.expneurol.2020.113492

Cited by 31 publications

(54 citation statements)

References 68 publications

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“…Overall, there were disruptions in cyclicity in all IHKA groups by one-and two-months post injection, but at four months only the IHKA-R animals showed significantly lengthened cycles in comparison to controls. These results confirm previous findings of estrous cycle disruption occurring by two months after injection in IHKA-R mice (Li et al, 2017(Li et al, , 2018(Li et al, , 2020 and demonstrate that disruption can also be seen at one and four months post-injection in this group. Furthermore, these results extend previous findings by indicating that IHKA-L mice follow similar trends as IHKA-R in cycle disruption for the first two months after injection.…”

Section: Estrous Cycles Are Longer In Ihka Micesupporting

confidence: 92%

Lateralized phenotypic differences after intrahippocampal kainic acid injection in female mice

Cutia

Leverton

et al. 2021

Preprint

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Clinical evidence indicates that patients with temporal lobe epilepsy (TLE) often show differential outcomes of comorbid conditions dependent on the lateralization of the seizure focus. However, whether a left or right seizure focus produces differential effects on comorbid outcomes has not been investigated in a rodent model of chronic recurrent seizures. Here, we used the intrahippocampal kainic acid (IHKA) mouse model of TLE to determine whether targeting of left or right dorsal hippocampus for injection produces different outcomes in hippocampal sclerosis, body weight gain, and multiple measures of reproductive endocrine dysfunction in female mice. At one, two, and four months after injection, in vivo measurements of estrous cycles and weight were followed by ex vivo examination of hippocampal sclerosis, circulating ovarian hormone and corticosterone levels, ovarian morphology, and pituitary gene expression. IHKA mice with right-targeted injection (IHKA-R) showed greater granule cell dispersion and pituitary Fshb expression compared to mice with left-targeted injection (IHKA-L). By contrast, pituitary expression of Lhb and Gnrhr were higher in IHKA-L mice compared to IHKA-R, but these values were not different from respective saline-injected controls. IHKA-L mice also showed an increased rate of weight gain compared to IHKA-R mice. Disruptions to estrous cyclicity, however, were similar in both IHKA-L and IHKA-R mice. These findings indicate that although major reproductive endocrine dysfunction phenotypes present similarly after targeting left or right dorsal hippocampus in the IHKA model of TLE, distinct latent mechanisms based on lateralization of seizure focus may contribute to produce similar emergent reproductive endocrine outcomes.

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Section: Estrous Cycles Are Longer In Ihka Micesupporting

confidence: 92%

Lateralized phenotypic differences after intrahippocampal kainic acid injection in female mice

Cutia

Leverton

et al. 2021

Preprint

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“…KA preparation KA monohydrate (#0222, Tocris Bioscience) was dissolved in 0.9% sterile saline and pH was adjusted to 7.4 with 20-30 µl 1 N NaOH (#SS266-1, Fisher Scientific) according to Tocris Bioscience's guidelines. The final concentration of the stock solution was 20 mM and it is similar to the concertation used by other investigators (Bui et al, 2018;Zeidler et al, 2018;Li et al, 2020). The stock solution was then sonicated for 1 hr to ensure good solubility as indicated in the manufacturer's recommendations.…”

Section: Kainic Acid (Ka) Injectionmentioning

confidence: 99%

“…Brief (3-7 sec) abnormalities were reported by others where they could be as frequent as 100 per hr (Kim et al, 2018; Sandau et al, 2019; Lai et al, 2020). Sometimes the EEG examples that were published suggested trains of spikes or epileptiform activity occurred in the wks after IHKA, but seizures were either rare, not shown, or the evidence that they occurred was not strong (e.g., Kiasalari et al, 2016; Zhu et al, 2016; Runtz et al, 2018; Bielefeld et al, 2019; Li et al, 2020). One study that described methods for IHKA in mice concluded that IHKA did not lead to epilepsy (Bielefeld et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

Lisgaras

Scharfman

2021

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Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this ambiguity, we slightly modified previous methods and employed continuous wideband video-EEG monitoring from 4 recording sites to best detect and characterize chronic epilepsy outcomes in both male and female mice. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 sec) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE.

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“…This was unexpected, as given the high mortality rate of the female heterozygous mice, we would have expected either increased seizure frequency or length as compared to males. It’s been shown that seizure burden in female mice is dependent on the phase of the reproductive cycle(29), and thus this may be contributing to the differences in seizure frequency we have reported. Others have reported differences between female and male DS mice, such as sex-dependent social interaction deficits(30) and increased mortality in females(11, 31).…”

Section: Discussionmentioning

confidence: 79%

Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome

Spink

et al. 2021

Preprint

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Dravet syndrome (DS) is a rare childhood epilepsy disorder resulting in spontaneous, recurrent seizures and behavioral co-morbidities. A successful drug screening model should recapitulate the phenotypes observed in a clinical setting. To facilitate the discovery and development of anti-seizure drugs for DS, the contract site of the NINDS Epilepsy Therapy Screening Program (ETSP) has continued to evaluate a mouse model of DS with a focus on evaluating behavioral phenotypes, spontaneous seizure activity, and sex-dependent differences. Scn1aA1783V/WT mice exhibited increased hyperactivity, thigmotaxis, and deficits in nest-building behavior. Ex-vivo brain slice electrophysiology experiments revealed increased excitability of hippocampal CA1 neurons specifically due to increased action potential firing frequency in response to brief depolarizations and decreased frequency of spontaneous GABAergic synaptic events. A video-EEG study revealed mice had on average, 1 seizure per day, with males seizing significantly more frequently than females. Increased proportion of seizure activity occurred during the dark phase of the light/dark cycle in both sexes. While clobazam, a drug commonly prescribed to patients with DS, had no effect on spontaneous seizure activity at the tested doses, the seizure history and frequency observed in this study aids in determining the sample sizes and experimental timeline needed for adequately powered preclinical drug studies. Overall, this study provides a broad description of the Scn1aA1783V/WT mouse and highlights the utility of this model in therapy discovery.

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Seizure burden fluctuates with the female reproductive cycle in a mouse model of chronic temporal lobe epilepsy

Cited by 31 publications

References 68 publications

Lateralized phenotypic differences after intrahippocampal kainic acid injection in female mice

Lateralized phenotypic differences after intrahippocampal kainic acid injection in female mice

Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

Evaluation of spontaneous seizure activity, sex-dependent differences, behavioral comorbidities, and alterations in CA1 neuron firing properties in a mouse model of Dravet Syndrome

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