Estrous cycle regulation of extrasynaptic δ-containing GABA(A) receptor-mediated tonic inhibition and limbic epileptogenesis.
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Results demonstrate the estrous cycle–related plasticity of neurosteroid-sensitive, δ-containing GABAA receptors that mediate tonic inhibition and seizure susceptibility in mice during diestrus.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 GABAA 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 GABAA 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 GABAA 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.read more
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References
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Book
The Mouse Brain in Stereotaxic Coordinates
TL;DR: The 3rd edition of this atlas is now in more practical 14"x11" format for convenient lab use and includes a CD of all plates and diagrams, as well as Adobe Illustrator files of the diagrams, and a variety of additional useful material.
Journal ArticleDOI
Modification of seizure activity by electrical stimulation. II. Motor seizure.
TL;DR: It was found that the development of motor seizures by stimulation of the amygdala resulted in an increased ability of the contralateral amygdala, and the septal area, but not of the hippocampus, to drive motor seizures when stimulated (“transfer”).
Journal ArticleDOI
Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.
John P. Lydon,Francesco J. DeMayo,C. R. Funk,Shailaja K. Mani,A. R. Hughes,C. A. Montgomery,Gopalan Shyamala,Orla M. Conneely,Bert W. O'Malley +8 more
TL;DR: Results provide direct support for progesterone's role as a pleiotropic coordinator of diverse reproductive events that together ensure species survival.
Journal ArticleDOI
Modification of seizure activity by electrical stimulation: III. Mechanisms
TL;DR: It was found that stimulation of more than one area increases the rate of seizure development, whereas disrupting inter-limbic connections retards seizure development.
Journal ArticleDOI
GABAA receptors : Immunocytochemical distribution of 13 subunits in the adult rat brain
TL;DR: The distribution of GABAA receptor subunits deriving from 13 different genes in the adult rat brain was investigated using immunocytochemistry, and striking examples of complementary distribution of certain subunit-immunoreactivities were observed.
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