Sex differences in the neurobiology of epilepsy: A preclinical perspective

Scharfman, Helen E.; MacLusky, Neil J.

doi:10.1016/j.nbd.2014.07.004

Cited by 130 publications

(125 citation statements)

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“…In previous studies in female Wistar rats, we showed that the natural changes in sex hormone levels during the estrous cycle do not affect seizure susceptibility in the amygdala kindling model of TLE [48]. More recently, we reported that the stage of estrous cycle had no obvious effect on onset, duration, or severity of kainate-induced SE in female HL-SD rats [49], which is consistent with observations of Scharfman and MacLusky [47]. Furthermore, the estrous cycle did not affect susceptibility of HL-SD rats to pentylenetetrazole [49], confirming previous experiments of Finn and Gee [50] in SD rats.…”

Section: Discussionsupporting

confidence: 90%

“…Except in one rat, SE could be induced on the morning of estrus, although significantly higher doses of pilocarpine were needed compared with those needed during other stages of the estrous cycle. The situation might have been different had SE not have been induced always at the same time of the day in the morning (as in the study of Scharfman et al [31]) but at time of peak estradiol and progesterone levels during the 4-to 5-day estrous cycle of the rat [47]. However, our main interest was to determine whether the estrous cycle increases variability in individual responses to pilocarpine that may be involved in the substrain differences observed in the present and previous studies in female SD and Wistar rats [14,15].…”

Section: Discussionmentioning

confidence: 98%

“…There is a long-held assumption that the estrous cycle of female rodents increases variability in various disease models, including epilepsy, which led to a sex bias in neuroscience and biomedical research [45][46][47]. However, the belief that female rats or mice are intrinsically more variable than males and too troublesome for routine inclusion in research protocols is without foundation [46].…”

Section: Discussionmentioning

confidence: 99%

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The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague–Dawley rats and the effect of estrous cycle

Brandt¹,

Bankstahl²,

Töllner³

et al. 2016

Epilepsy & Behavior

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague–Dawley rats and the effect of estrous cycle

Brandt¹,

Bankstahl²,

Töllner³

et al. 2016

Epilepsy & Behavior

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“…By contrast, exposure to estradiol can suppress GABAergic inhibition of hippocampal neurons (Huang and Woolley, 2012). Consistent with these findings, estradiol can impact seizure susceptibility (Scharfman and MacLusky, 2014; Reddy, 2017). In addition, several studies have identified sex difference in mTOR signaling in non-CNS tissues and functions (Gürgen et al, 2013; Miller et al, 2014; Baar et al, 2016).…”

Section: Introductionsupporting

confidence: 70%

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

Santos

Pun

Arafa

et al. 2017

Neurobiology of Disease

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Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity.

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confidence: 99%

The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

Galanopoulou¹

2015

Epilepsy Curr

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CommentaryHormones influence neuronal excitability and seizure susceptibility in both adulthood and during development (1)(2)(3)(4)(5)(6)(7)(8). A paradigm illustrating these interactions is catamenial epilepsy, where seizures may cluster around specific periods of the menstrual cycle (3). The perimenstrual (C1) type of catamenial epilepsy is a type of epilepsy in which seizures cluster around the menstrual phase when estradiol, progesterone, as well as the neurosteroid allopregnanolone decline. Allopregnanolone is a progesterone metabolite known to act on GABA A receptors. Progesterone is converted to 5a-dihydroprogesterone (5a-DHP) by 5a-reductase, and then 5a-DHP is converted to allopregnanolone by 3b-hydroxysteroid dehydrogenase (3b-HSD).Reddy's team has been a pioneer in studies aiming to shed light in the molecular and pathophysiological mechanisms of increased seizure susceptibility in perimenstrual epilepsy. To recreate the hormonal and neurosteroid changes occurring during this perimenstrual period, they introduced a model of neurosteroid withdrawal (NSW) in adult female mice by administering high dose progesterone twice daily for 7 days followed by finasteride, a 5a-reductase inhibitor that blocks neurosteroid synthesis (8). This NSW model recreates high levels of allopregnanolone during the progesterone administration phase, which rapidly decline to normal levels during NSW. Interestingly, NSW mice demonstrate increased susceptibility to kindling associated with increased expression of the a4 GABA A receptor subunit in the dentate gyrus granule cells (8). The Carver et al. study completes these findings by showing a parallel increased expression of the d GABA A receptor subunit, a common partner of a4 in extrasynaptic GABA A receptors, as well as enhanced allopregnanolone potentiation of tonic but also phasic GABA A receptor currents in NSW mice. Such findings would be normally considered as capable of evoking antiseizure effects by increasing tonic inhibition. However, the authors found smaller tonic GABA current shifts in NSW granule cells compared to controls in the absence of added GABA, possibly suggesting the existence of silent GABA A receptors or low extracellular GABA in NSW hippocampus. In d knock-out Neurosteroids are endogenous regulators of neuronal excitability and seizure susceptibility. Neurosteroids, such as allopregnanolone (AP; 3α-hydroxy-5α-pregnan-20-one), exhibit enhanced anticonvulsant activity in perimenstrual catamenial epilepsy, a neuroendocrine condition in which seizures are clustered around the menstrual period associated with neurosteroid withdrawal (NSW). However, the molecular mechanisms underlying such enhanced neurosteroid sensitivity remain unclear. Neurosteroids are allosteric modulators of both synaptic (αβγ2-containing) and extrasynaptic (αβδ-containing) GABA A receptors, but they display greater sensitivity toward δ-subunit receptors in dentate gyrus granule cells (DGGCs). Here we report a novel plasticity of extrasynaptic δ-containing GABA A receptors in the den...

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Sex differences in the neurobiology of epilepsy: A preclinical perspective

Cited by 130 publications

References 113 publications

The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague–Dawley rats and the effect of estrous cycle

The pilocarpine model of temporal lobe epilepsy: Marked intrastrain differences in female Sprague–Dawley rats and the effect of estrous cycle

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

The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

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