The Role of the δ GABA(A) Receptor in Ovarian Cycle-Linked Changes in Hippocampus-Dependent Learning and Memory

The delta subunit of the GABA(A)R is highly expressed in the dentate gyrus of the hippocampus where it mediates a tonic extrasynaptic inhibitory current that is sensitive to neurosteroids. In female mice, the expression level of the delta subunit within the dentate gyrus is elevated in the diestrous relative to estrous phase of the estrous cycle. Previous work in our lab found that female delta-GABA(A)R KO mice showed enhanced hippocampus-dependent trace but normal hippocampus-independent delay fear conditioning. Wild-type females in this study showed a wide range of freezing levels, whereas delta-GABA(A)R KO mice expressed only high levels of fear. We hypothesized that the variability in the wild-type mice may have been due to estrous cycle-mediated changes in the expression of the delta-GABA(A)R, with low levels of freezing in mice that were in the diestrous phase when dentate gyrus tonic inhibition is high. In the present study we tested this hypothesis by utilizing contextual, delay, and trace fear conditioning protocols in mice that were trained and tested in either the diestrous or estrous phases. Consistent with our hypothesis, we found a significant impairment of hippocampus-dependent learning and memory during diestrus relative to estrus in wild-type mice and this impairment was absent in delta-GABA(A)R mice. These findings argue that the delta-GABA(A)R plays an important role in estrous cycle-mediated fluctuations in hippocampus-dependent learning and memory.