Ovarian cycle-linked changes in GABA(A) receptors mediating tonic inhibition alter seizure susceptibility and anxiety.
Disturbances of neuronal excitability changes during the ovarian cycle may elevate seizure frequency in women with catamenial epilepsy and enhance anxiety in premenstrual dysphoric disorder (PMDD). The mechanisms underlying these changes are unknown, but they could result from the effects of fluctuations in progesterone-derived neurosteroids on the brain. Neurosteroids and some anxiolytics share an important site of action: tonic inhibition mediated by delta subunit-containing GABA(A) receptors (deltaGABA(A)Rs). Here we demonstrate periodic alterations in specific GABA(A)R subunits during the estrous cycle in mice, causing cyclic changes of tonic inhibition in hippocampal neurons. In late diestrus (high-progesterone phase), enhanced expression of deltaGABA(A)Rs increases tonic inhibition, and a reduced neuronal excitability is reflected by diminished seizure susceptibility and anxiety. Eliminating cycling of deltaGABA(A)Rs by antisense RNA treatment or gene knockout prevents the lowering of excitability during diestrus. Our findings are consistent with possible deficiencies in regulatory mechanisms controlling normal cycling of deltaGABA(A)Rs in individuals with catamenial epilepsy or PMDD.
Maguire
Jamie L
JL
Department of Neurology, The David Geffen School of Medicine, University of California Los Angeles, 710 Westwood Plaza, Los Angeles, California 90095, USA.
Stell
Brandon M
BM
Rafizadeh
Mahsan
M
Mody
Istvan
I
D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003292:Convulsants / Q000494:pharmacology; D015536:Down-Regulation / Q000235:genetics; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D030762:Estrous Cycle / Q000378:metabolism*; D005260:Female; D058787:GABA-A Receptor Antagonists; D020022:Genetic Predisposition to Disease / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000235:genetics*; D016376:Oligonucleotides, Antisense; D009924:Organ Culture Techniques; D011293:Premenstrual Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D011374:Progesterone / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D003292:Convulsants; D058787:GABA-A Receptor Antagonists; D012739:Gonadal Steroid Hormones; D016376:Oligonucleotides, Antisense; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011374:Progesterone