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

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.

Section: Methodsmentioning

confidence: 99%

A Mouse Kindling Model of Perimenstrual Catamenial Epilepsy

Reddy

Gould²,

Gangisetty³

2012

“…The mouse kindling model of epilepsy was used for the evaluation of protective effect of GX and its analogs. Surgical procedures and drug testing protocols in the hippocampus kindling model were conducted as described previously (Reddy and Mohan, 2011;Reddy et al, 2015;.…”

Section: Jpet #246660mentioning

confidence: 99%

3β-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynapticδ-Subunitγ-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield

Chuang

Reddy

2018

“…The rapid kindling model of epileptogenesis was used for assessment of seizure susceptibility over the estrous cycle. Rapid kindling allows accelerated evaluation of experimental manipulations during the progression of epilepsy induction (Lothman and Williamson, 1993;Reddy and Mohan, 2011). The rapid kindling procedure was similar to the conventional kindling with daily stimulations except that stimulations were applied every 30 minutes until mice exhibited consistent stage 5 seizures.…”

Section: Behavioral Studiesmentioning

confidence: 99%

“…Progesterone is a precursor for the synthesis of neurosteroids such as allopregnanolone (AP) in the brain (Reddy and Mohan, 2011). These neurosteroids are increased in parallel to their precursor progesterone during the menstrual cycle (Tuveri et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Estrous Cycle Regulation of Extrasynaptic δ-Containing GABA_A Receptor-Mediated Tonic Inhibition and Limbic Epileptogenesis

Gangisetty

Carver

et al. 2013

137

The ovarian cycle affects susceptibility to behavioral and neurologic conditions. The molecular mechanisms underlying these changes are poorly understood. Deficits in cyclical fluctuations in steroid hormones and receptor plasticity play a central role in physiologic and pathophysiologic menstrual conditions. It has been suggested that synaptic GABA A receptors mediate phasic inhibition in the hippocampus and extrasynaptic receptors mediate tonic inhibition in the dentate gyrus. Here we report a novel role of extrasynaptic d-containing GABA A receptors as crucial mediators of the estrous cycle-related changes in neuronal excitability in mice, with hippocampus subfield specificity. In molecular and immunofluorescence studies, a significant increase occurred in d-subunit, but not a4-and g2-subunits, in the dentate gyrus during diestrus. However, d-subunit upregulation was not evident in the CA1 region. The d-subunit expression was undiminished by age and ovariectomy and in mice lacking progesterone receptors, but it was significantly reduced by finasteride, a neurosteroid synthesis inhibitor. Electrophysiologic studies confirmed greater potentiation of GABA currents by progesterone-derived neurosteroid allopregnanolone in dissociated dentate gyrus granule cells in diestrus than in CA1 pyramidal cells. The baseline conductance and allopregnanolone potentiation of tonic currents in dentate granule cells from hippocampal slices were higher than in CA1 pyramidal cells. In behavioral studies, susceptibility to hippocampus kindling epileptogenesis was lower in mice during diestrus. These results demonstrate the estrous cycle-related plasticity of neurosteroidsensitive, d-containing GABA A receptors that mediate tonic inhibition and seizure susceptibility. These findings may provide novel insight on molecular cascades of menstrual disorders like catamenial epilepsy, premenstrual syndrome, and migraine.