Glucocorticoid Receptor Translational Isoforms Generate Unique Glucocorticoid Responses in the Mouse Brain

Glucocorticoids are primary stress hormones necessary for life that act on nearly every tissue in the body to maintain homeostasis. These hormones and their synthetic derivatives are widely used in the clinic to combat disease but are limited by serious adverse effects. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). In addition to the classic full-length receptor (GR-A), seven highly conserved receptor isoforms with progressively shorter N-terminal transactivation domains (NTD) (GR-B, GR-C1, GR-C2, GR-C3, GR-D1, GR-D2, GR-D3) are produced from the single GR gene by alternative translation initiation. To investigate the physiological function of these isoforms, we developed knockin mice that express GR-A but lack the GR NTD translational isoforms. Analyses of the hippocampal transcriptome from wild-type and GR-A knockin mice treated with dexamethasone (Dex) revealed three classes of Dex-regulated genes: genes dependent on GR-A alone, genes dependent on the GR NTD translational isoforms, and genes dependent on GR-A only under conditions of GR NTD isoform deficiency. The genes dependent on the GR NTD isoforms were preferentially associated with circadian rhythm signaling, synaptic function, and cognition. Consistent with these gene enrichment results, the GR-A knockin mice exhibited alterations in hypothalamic-pituitary-adrenal axis activity and fear-motivated contextual learning. The GR NTD translational isoforms formed distinct molecular complexes with GR-A and with each other, providing a mechanistic basis for their unique transcriptional signatures. These findings demonstrate that the GR NTD translational isoforms contribute to the actions of glucocorticoids in the brain by generating heterogeneity in glucocorticoid signaling.