SAT-005 Gene Expression and Behavioral Alterations in Mice with Conditional Knockout of GR, MR, or Both GR and MR in the Hippocampus

Glucocorticoids are primary stress hormones that regulate brain function. Aberrant levels of these steroids have been implicated in the pathogenesis of cognitive impairments and psychiatric disorders. Glucocorticoids exert their effects on cells via binding the glucocorticoid receptor (GR) and the closely related mineralocorticoid receptor (MR). A distinctive feature of the hippocampus is that it expresses high levels of both GR and MR. However, the specific roles played by these receptors in mediating the direct actions of glucocorticoids in the hippocampus are poorly understood. To elucidate the in vivo function of hippocampal GR and MR, we employed emx1-cre mice to ablate GR (hippocampal GRKO), MR (hippocampal MRKO), or both GR and MR (hippocampal GRMRdKO) in the hippocampus. The single and double knockout mice were born at the expected Mendelian ratio and survived normally through 12 months of age. Small reductions in body weight were observed for the hippocampal MRKO and hippocampal GRMRdKO mice, but not the hippocampal GRKO mice. RNA sequencing performed on hippocampal RNA revealed major differences in both the basal and glucocorticoid regulated transcriptome in the single and double knockout mice. In behavioral assays, all three mutant mice exhibited reduced anxiety in the marble burying test. However, only the hippocampal MRKO and hippocampal GRMRdKO mice showed decreased anxiety in the elevated plus maze and open field tests. A forced swim test revealed no genotype differences in depression-like behavior. In a conditioned fear test, the hippocampal GRKO mice showed a reduction in context-dependent learning whereas the hippocampal MRKO and hippocampal GRMRdKO mice showed an increase in cue-dependent learning. These findings demonstrate that GR and MR regulate both common and unique signaling pathways in the hippocampus that influence anxiety and learning and memory.