Dyrk1A mediated epigenetic alterations in the prefrontal cortex contribute to cognitive impairment in depression

초록

Dyrk1A is a key player in gene regulation, modifying RNA Polymerase II (RNAPII) and affecting its interaction with gene promoters. While Dyrk1A is associated with intellectual disabilities, its epigenetic role in depression remains unclear. In our study, we investigated Dyrk1A's epigenetic role in a chronic social defeat stress (CSDS) model. Using magnetic resonance imaging, we observed reduced activity in the prefrontal cortex (PFC) in CSDS-susceptible mice. However, inhibiting Dyrk1A pharmacologically restored PFC activity to control levels. Inhibition of Dyrk1A specifically in the PFC reversed CSDS-induced depressive behavior, while Dyrk1A overexpression worsened depressive behavior even in less severe stress conditions. Additionally, increased Dyrk1A expression resulted in significant cognitive deficit with depressive behavior, which improved upon Dyrk1A inhibition. However, in female, Dyrk1A overexpression led to depression but not cognitive deficit. Together, our study found that Dyrk1A enhances RNAPII recruitment to the MAO-A promoter, increasing MAO-A transcription and serotonin degradation, contributing to the development of cognitive deficit with depression in male mice.