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

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Abstract

The δ subunit of the GABAAR 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 δ 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 δ-GABAAR 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 δ-GABAAR 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 δ-GABAAR, 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 δ-GABAAR mice. These findings argue that the δ-GABAAR plays an important role in estrous cycle-mediated fluctuations in hippocampus-dependent learning and memory.

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Acknowledgments

We would like to thank the following funding sources for their financial support: NIH Grants: MH62122, AA07680 and NS35985; Training Grants: 5T32MH019384-14. We would also like to thank Sarah Madsen for her expert technical assistance and Jamie Maguire for training in estrous cycle monitoring.

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Authors and Affiliations

  1. Department of Psychology, Brain Research Institute, University of California Los Angeles, 8578 Franz Hall, Los Angeles, CA, 90095-1563, USA

    Jesse D. Cushman & Michael S. Fanselow

  2. Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Mellissa D. Moore & Richard W. Olsen

Authors
  1. Jesse D. Cushman
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  2. Mellissa D. Moore
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  3. Richard W. Olsen
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  4. Michael S. Fanselow
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Correspondence to Jesse D. Cushman.

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Cushman, J.D., Moore, M.D., Olsen, R.W. et al. The Role of the δ GABA(A) Receptor in Ovarian Cycle-Linked Changes in Hippocampus-Dependent Learning and Memory. Neurochem Res 39, 1140–1146 (2014). https://doi.org/10.1007/s11064-014-1282-6

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  • DOI: https://doi.org/10.1007/s11064-014-1282-6

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