The role of hippocampal α2‐containing GABAA receptors in benzodiazepine‐induced anxiolysis

Abstract

While the hippocampus was granted a central role in the neurobiology of anxiety in early theories, later findings shifted the attention to other structures and left the role of hippocampus in anxiety and anxiolysis a controversial subject. α2‐containing GABAA receptors mediate benzodiazepine‐induced anxiolysis in models of unconditioned anxiety and conditioned fear. To investigate whether the α2‐containing GABAA receptors within hippocampal circuits contribute to this effect, we generated mice that lack these receptors selectively in the pyramidal cells of the CA1 or the CA3, or in the granule cells of the dentate gyrus (CA1‐ KO, CA3‐KO and DG‐KO, respectively). In models of unconditioned anxiety, such as the elevated plus maze, CA1‐KO mice showed diazepam‐induced anxiolysis similar to wild types. This effect, however, was abolished in CA3‐KO and DG‐KO mice. Conversely, in models of conditioned fear, such as fear‐potentiated startle, CA1‐KO mice failed to show the anxiolytic effects of diazepam, while CA3‐KO and DG‐KO were comparable to wild types. Our findings suggest that the inhibition of the trisynaptic hippocampal pathway is required for diazepam anxiolysis in unconditioned anxiety models, while the inhibition of the CA1 output to entorhinal cortex and downstream structures is required for diazepam‐induced reduction of conditioned fear.