High seizure frequency during certain phases of the menstrual cycle in women with catamenial epilepsy and increased anxiety in premenstrual dysphoric disorder (PMDD) “may both result from disturbances of normal changes in neuronal excitability during the ovarian cycle,” remarked Istvan Mody, PhD, lead author of the study, which was reported in the May 15 online Nature Neuroscience. The findings could lead to novel therapies for these and other central nervous system disorders associated with the menstrual cycle. They may also be applicable to postpartum depression and mood swings during pregnancy, and may explain how stress hormones affect the brain, Dr. Mody noted.

FLUCTUATING SUSCEPTIBILITY

“Patients with PMDD have a much higher incidence of catamenial epilepsy than the general population and exhibit increased luteal phase [neuronal] excitability, suggesting that these two disorders may share a similar pathologic mechanism,” Dr. Mody explained. Hypothesizing that this mechanism might be driven by the effects of fluctuations in progesterone-derived neurosteroids on the brain, Dr. Mody and colleagues studied changes in γ-aminobutyric acid (GABA) brain receptors during the estrous cycle in mice. They found that periodic alterations in specific GABA_A receptor δ subunits “resulted in changes in the tonic inhibition of dentate gyrus granule cells, seizure susceptibility, and anxiety levels.” Further, eliminating the cycling of these δ subunits by antisense treatment or gene knockout prevented a reduction of neuronal excitability common to late diestrus—a period characterized by diminished seizure susceptibility and anxiety levels in patients with catamenial epilepsy or PMDD, they reported.

“Our data are consistent with possible deficiencies in regulatory mechanisms controlling expression of δ subunit–containing GABA_A receptors during the ovarian cycle in catamenial epilepsy and PMDD patients,” said Dr. Mody, Coelho Professor of Neurology at the Reed Neurological Research Center at the David Geffen School of Medicine at the University of California, Los Angeles.

CYCLING AHEAD

The next step will be to determine the precise mechanisms behind these changes, Dr. Mody said. “We have to find the molecular identities of the players responsible for changing the number of these receptors on the surface of nerve cells. This may be quite relevant to the way nerve cells respond to stimuli in the human brain during the menstrual cycle; if some of our findings are replicated in humans, our study would provide some testable predictions about new therapies.”

Suggested Reading
Maguire JL, Stell BM, Rafizadeh M, Mody I. Ovarian cycle–linked changes in GABAA receptors mediating tonic inhibition alter seizure susceptibility and anxiety. Nat Neurosci. 2005. E-pub ahead of print.

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