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The Journal of Neuroscience, February 28, 2007, 27(9):2155-2162; doi:10.1523/JNEUROSCI.4945-06.2007

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Cellular/Molecular
Neurosteroid Synthesis-Mediated Regulation of GABA_A Receptors: Relevance to the Ovarian Cycle and Stress

Jamie Maguire and Istvan Mody

Departments of Neurology and Physiology, The David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095

Correspondence should be addressed to Dr. Istvan Mody, Department of Neurology, Neuroscience Research Building 1, Room 575D, The David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive South, Los Angeles, CA 90095. Email: mody{at}ucla.edu

Recently, we demonstrated cyclic alterations in GABA_A receptor (GABA_AR) subunit composition over the ovarian cycle correlated with fluctuations in progesterone levels. However, it remains unclear whether this physiological regulation of GABA_ARs is directly mediated by hormones. Here, we show that both ovarian and stress hormones are capable of reorganizing GABA_ARs by actions through neurosteroid metabolites. The cyclic alterations in GABA_ARs demonstrated in female mice can be mimicked with exogenous progesterone treatment in males or in ovariectomized females. Progesterone (5 mg/kg, twice daily) upregulates the expression of GABA_AR subunits and enhances the tonic inhibition mediated by these receptors in dentate gyrus granule cells (DGGCs). These changes in males as well as ovarian cycle-induced changes in females can be blocked by finasteride, an antagonist of neurosteroid synthesis from progesterone. The altered GABA_AR expression is unaffected by the progesterone receptor antagonist RU486 [mifepristone (11ß-[p-(dimethylamino)phenyl]-17ß-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], suggesting that neurosteroid synthesis and not progesterone receptor activation underlies the hormone-mediated effects on GABA_AR expression. Neurosteroids can alter GABA_AR expression on a rapid timescale, because GABA_AR upregulation can be induced in brain slices maintained in vitro after a short (30 min) treatment with the neurosteroid 3,5-tetrahydrodeoxycorticosterone (THDOC) (100 nM). Consistent with these rapid alterations, acute stress, a condition known to quickly raise THDOC levels, within 30 min induces upregulation of GABA_AR subunit expression and increase tonic inhibition in DGGCs. These results reveal that several physiological conditions characterized by elevations in neurosteroid levels induce a reorganization of GABA_ARs through the action of neurosteroids.

Key words: GABA_ARs; progesterone; neurosteroids; plasticity; stress; ovarian cycle

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Received Nov. 14, 2006; revised Jan. 8, 2007; accepted Jan. 15, 2007.

Correspondence should be addressed to Dr. Istvan Mody, Department of Neurology, Neuroscience Research Building 1, Room 575D, The David Geffen School of Medicine, University of California, Los Angeles, 635 Charles Young Drive South, Los Angeles, CA 90095. Email: mody{at}ucla.edu

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