ArticleThe Journal of pharmacology and experimental therapeutics2013
Estrous cycle regulation of extrasynaptic δ-containing GABA(A) receptor-mediated tonic inhibition and limbic epileptogenesis.
Article in The Journal of pharmacology and experimental therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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Who cites it
62 citing papers in PubMed, 90 citations in OpenAlex.
- Article
- Steroid 5α-reductases in the brain: From neurosteroidogenesis to therapeutic implications.Frontiers in neuroendocrinology · 2026Review
- Neurosteroid mitigation of developmental neurological dysfunction, long-term epileptic biomarkers, chronic neuroinflammation, and neurodegeneration in a pediatric rat model of organophosphate exposure.The Journal of pharmacology and experimental therapeutics · 2025Article
- GABA system as the cause and effect in early development.Neuroscience and biobehavioral reviews · 2024Review
- Sex Differences in Organophosphate Model of Benzodiazepine-Refractory Status Epilepticus and Neuronal Damage.The Journal of pharmacology and experimental therapeutics · 2024Article
- Neuroprotectant Activity of Novel Water-Soluble Synthetic Neurosteroids on Organophosphate Intoxication and Status Epilepticus-Induced Long-Term Neurological Dysfunction, Neurodegeneration, and Neuroinflammation.The Journal of pharmacology and experimental therapeutics · 2024Article
- Neurosteroids as Novel Anticonvulsants for Refractory Status Epilepticus and Medical Countermeasures for Nerve Agents: A 15-Year Journey to Bring Ganaxolone from Bench to Clinic.The Journal of pharmacology and experimental therapeutics · 2024Review
- Preclinical and clinical pharmacology of brexanolone (allopregnanolone) for postpartum depression: a landmark journey from concept to clinic in neurosteroid replacement therapy.Psychopharmacology · 2023Review
- The impact of the ovarian cycle on anxiety, allopregnanolone, and corticotropin releasing hormone changes after motherhood in female rats and women.Translational psychiatry · 2023Article
- Isobolographic analysis of adjunct antiseizure activity of the FDA-approved cannabidiol with neurosteroids and benzodiazepines in adult refractory focal onset epilepsy.Experimental neurology · 2023Article
- Role of allopregnanolone-mediated γ-aminobutyric acid A receptor sensitivity in the pathogenesis of premenstrual dysphoric disorder: Toward precise targets for translational medicine and drug development.Frontiers in psychiatry · 2023Review
- The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling.Nature communications · 2022Article
- Factors not considered in the study of drug-resistant epilepsy: Psychiatric comorbidities, age, and gender.Epilepsia open · 2022Review
- Neurosteroid replacement therapy for catamenial epilepsy, postpartum depression and neuroendocrine disorders in women.Journal of neuroendocrinology · 2022Review
- Physiological markers of rapid antidepressant effects of allopregnanolone.Journal of neuroendocrinology · 2022Review
- Article
- GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan.Frontiers in behavioral neuroscience · 2022Review
- Molecular mechanisms of sex differences in epilepsy and seizure susceptibility in chemical, genetic and acquired epileptogenesis.Neuroscience letters · 2021Review
- Progesterone modulates neuronal excitability bidirectionally.Neuroscience letters · 2021Review
- Cerebellum-Specific Deletion of the GABACell reports · 2020Article
2 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
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 δ-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 δ-subunit, but not α4- and γ2-subunits, in the dentate gyrus during diestrus. However, δ-subunit upregulation was not evident in the CA1 region. The δ-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 neurosteroid-sensitive, δ-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.