ANDROGENS AND NEURONAL ACTIVITY SYNERGISTICALLY ACT ON ANDROGEN RECEPTOR TO MODULATE THE IMMEDIATE TRANSCRIPTIONAL RESPONSE TO STIMULATION

Neurons are excitable cells that need to rapidly translate electrochemical inputs into a precise gene expression program, named immediate transcriptional response to stimulus. It is an integral part of the neuronal response to environmental stimulation and serves many brain processes, including development, learning, and response to injury and drugs. Aberrance happening at this step can lead to neuron dysfunction and abnormal responses. Androgen Receptor (AR) is a disease-relevant TF that drives neuron degeneration when mutated. It is a steroid hormone-activated transcription factor located in the cytoplasm when inactive and translocates to the nucleus upon androgen binding, where it regulates the expression of specific AR target genes. We assessed whether AR acts as an activity-dependent transcription factor. We found that, upon ligand binding, neuron depolarization leads to the rapid phosphorylation of AR to specific serine/proline sites necessary for its immediate activation. This translates into an AR-driven expression of specific immediate early genes (IEGs), which in turn control the expression of late response genes (LRGs) to instate a long-lasting biological effect. Interestingly, few of the most upregulated genes – directly bound by AR - were already known to be key players of the immediate transcriptional response, such as Npas4, cFos and Fosb. These results suggested a novel role for AR as activity-dependent transcription factor, providing new insights on how neurons integrate sex hormonal signals with neuronal activity. PolyQ expanded-AR is hyperphosphorylated and this fine mechanism of regulation is lost. This leads to an aberrant gene expression regulation of the downstream target genes.