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Development and persistence of limbic epileptogenesis are impaired in mice lacking progesterone receptors.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2011 Jan 12; Vol. 31 (2), pp. 650-8. - Publication Year :
- 2011
-
Abstract
- Progesterone plays a key role in ovarian cycle-related synaptic plasticity and neuronal excitability. Progesterone receptors (PRs), which mediate the cellular actions of progesterone, are expressed in the hippocampus and other limbic regions, but their functional significance remains unknown. Here, we report a novel role of PRs as crucial mediators in the development of epileptogenesis, which is the process whereby a normal brain becomes progressively epileptic because of precipitating factors. The PR knock-out (PR(-/-)) mouse, which lacks both the PR-A and PR-B isoforms, exhibited an increased resistance to epileptogenesis in the hippocampus and amygdala kindling models. Lack of PRs markedly impaired the persistence of seizure expression at 4 weeks after kindling development. We further show that selective inhibition of PRs in the brain by antisense oligos or pharmacological blockade of PRs by RU-486 [11β-[p-(dimethylamino)phenyl]-17β-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one] resulted in a significant decrease in epileptogenesis in wild-type (PR(+/+)) mice. The delayed epileptogenesis in PR knock-out mice was not substantially affected by inhibition of neurosteroid synthesis. Mice lacking PRs show supersensitivity to the antiseizure responses of progesterone. Collectively, these results suggest that PRs in the hippocampus are linked to signaling pathways that control susceptibility to epileptogenesis and possibly persistence of an epileptic-like state. The PR pathway may represent a unique target for preventing or retarding epileptogenesis in females.
- Subjects :
- Animals
Anticonvulsants pharmacology
Disease Susceptibility
Epilepsy etiology
Epilepsy pathology
Female
Gene Knockdown Techniques
Hippocampus pathology
Kindling, Neurologic
Limbic System pathology
Mice
Mice, Knockout
Mifepristone pharmacology
Neurosecretory Systems pathology
Neurotransmitter Agents biosynthesis
Oligonucleotides, Antisense pharmacology
Progesterone metabolism
Progesterone pharmacology
Receptors, Progesterone antagonists & inhibitors
Receptors, Progesterone genetics
Signal Transduction
Epilepsy physiopathology
Limbic System physiopathology
Receptors, Progesterone physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 31
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 21228174
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.4488-10.2011