Neurosteroid withdrawal regulates GABA-A receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway

Gangisetty, Omkaram; Reddy, Doodipala Samba

doi:10.1016/j.neuroscience.2010.07.037

Cited by 81 publications

(107 citation statements)

References 81 publications

(148 reference statements)

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“…Electrode implantation and stimulation procedures for mouse hippocampus kindling were performed as described previously (Gangisetty and Reddy, 2010). Mice were anesthetized by intraperitoneal injection of a mixture of ketamine (100 mg/kg) and xylazine (10 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, perimenstrual seizure exacerbations may be caused by withdrawal of the antiseizure effects of neurosteroids (Reddy, 2009). Neurosteroid withdrawal is associated with a marked up-regulation of the ␣4 subunit in the hippocampus (Smith et al, 1998a,b), which is associated with an increase in seizure susceptibility and benzodiazepine resistance Gangisetty and Reddy, 2010). Thus, neurosteroid withdrawal may be a key triggering factor for catamenial seizure exacerbations.…”

Section: Introductionmentioning

confidence: 99%

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A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

J Pharmacol Exp Ther

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Catamenial epilepsy is caused by fluctuations in progesteronederived GABA A receptor-modulating anticonvulsant neurosteroids, such as allopregnanolone, that play a significant role in the pathophysiology of epilepsy. However, there is no specific mouse model of catamenial epilepsy. In this study, we developed and characterized a mouse model of catamenial epilepsy by using the neurosteroid-withdrawal paradigm. It is hypothesized that seizure susceptibility decreases when neurosteroid levels are high (midluteal phase) and increases during their withdrawal (perimenstrual periods) in close association with GABA A receptor plasticity. A chronic seizure condition was created by using the hippocampus kindling model in female mice. Elevated neurosteroid levels were induced by sequential gonadotropin treatment, and withdrawal was induced by the neurosteroid synthesis inhibitor finasteride. Elevated neurosteroid exposure reduced seizure expression in fully kindled mice. Fully kindled mice subjected to neurosteroid withdrawal showed increased generalized seizure frequency and intensity and enhanced seizure susceptibility. They also showed reduced benzodiazepine sensitivity and enhanced neurosteroid potency, similar to the clinical catamenial seizure phenotype. The increased susceptibility to seizures and alterations in antiseizure drug responses are associated with increased abundance of the ␣4 and ␦ subunits of GABA A receptors in the hippocampus. These findings demonstrate that endogenous neurosteroids protect against seizure susceptibility and their withdrawal, such as that which occurs during menstruation, leads to exacerbation of seizure activity. This is possibly caused by specific changes in GABA A receptor-subunit plasticity and function, therefore providing a novel mouse model of human perimenstrual catamenial epilepsy that can be used for the investigation of disease mechanisms and new therapeutic approaches.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

J Pharmacol Exp Ther

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“…Relative seizure resistance in mice lacking PRs or finasterideinduced increase in seizure susceptibility in WT mice is consistent with such dual pathways. These mechanisms may be relevant to the pathophysiology of catamenial epilepsy (Scharfman and MacLusky, 2006;Reddy, 2009;Gangisetty and Reddy, 2010).…”

Section: P Regulates Seizure Susceptibility Via Prs: Pathophysiologicmentioning

confidence: 99%

Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors

Reddy¹,

Mohan²

2011

J. Neurosci.

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“…How does the brain sense this homeostatic change and adopt patterns of signaling that are defined by recent homeostatic changes? The authors previously provided evidence that NSW induces early growth response factor 3 (Egr3), leading to upregulation of the a4 subunit and increasing seizure susceptibility (8). The exact signaling pathway that leads to upregulation of d subunits is less clear.…”

Section: The Perimenstrual Delta Force: a Trojan Horse For Neurosteromentioning

confidence: 99%

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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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Neurosteroid withdrawal regulates GABA-A receptor α4-subunit expression and seizure susceptibility by activation of progesterone receptor-independent early growth response factor-3 pathway

Cited by 81 publications

References 81 publications

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Development and Persistence of Limbic Epileptogenesis Are Impaired in Mice Lacking Progesterone Receptors

The Perimenstrual Delta Force: A Trojan Horse for Neurosteroid Effects

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