Cycles and seizures

Reporting in Nature Neuroscience, Maguire and colleagues show that cyclic alterations in the levels of steroid hormones during the oestrus cycle in mice are associated with changes in the subunit composition of GABA_A (γ-aminobutyric acid type A) receptors (GABA_ARs), and that these alterations seem to be responsible for periodic changes in seizure susceptibility and anxiety.

GABA_ARs that contain δ-subunits (δGABA_ARs) mediate tonic inhibition in many neurons, including dentate gyrus granule cells, and are sensitive to neurosteroids. Using western blot analysis, Maguire et al. found that the expression of δGABA_ARs in the hippocampus was much higher during late dioestrus, when progesterone concentrations are high, than during oestrus, when circulating progesterone is lower.

Consistent with the modifications of receptor subunit composition, granule cells from the dentate gyrus showed a twofold higher tonic conductance during late dioestrus than during oestrus. However, synaptic GABA_AR function, as measured by spontaneous inhibitory postsynaptic potentials, did not change across the oestrus cycle.

Female mice are relatively resistant to seizures induced by kainic acid during dioestrus compared with oestrus, and are also more anxious during oestrus. To show a link between the reorganization of GABA_ARs and seizure susceptibility, the authors used mice in which δGABA_AR expression was reduced by antisense mRNA or abolished by gene knockout. When antisense mRNA was used to prevent the normal upregulation of δGABA_ARs during late dioestrus, the tonic inhibitory current was not increased, and seizure susceptibility increased to a degree similar to that found during oestrus.

Consistent with this finding, Gabrd-knockout mice, in which δGABA_AR expression is abolished, did not show the normal lowering of seizure susceptibility during dioestrus. These findings support the idea that the cyclical reorganization of GABA_AR subunit composition leads to alterations in neuronal excitability and susceptibility to seizures.

These findings have important clinical implications. In humans, hormonal changes during the ovarian cycle can be associated with clusters of seizures (catamenial epilepsy) or with increased anxiety (premenstrual dysphoric disorder). These symptoms might result, at least in part, from cyclical changes in δGABA_AR expression, and these receptor subunits could, therefore, be a therapeutic target.