Dyrk1A-Induced Epigenetic Alterations in the Prefrontal Cortex Contribute to Cognitive Impairment in Depression

초록

Dyrk1A (Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A), crucially regulates gene expression by interacting with and phosphorylating the carboxy-terminal domain of RNA polymerase II (RNAP II), impacting its association with target promoters. Although Dyrk1A is associated with a variety of intellectual disabilities, epigenetic modification in Dyrk1A associated with cogtive impairment in depression largely unknown. In this study, we investigated the epigenetic role of Dyrk1A in an animal model of chronic social defeat stress (CSDS). Using manganese-enhanced magnetic resonance imaging, we observed reduced prefrontal frontal cortex (PFC) activity in CSDS susceptible individuals, while pharmacological inhibition of Dyrk1A increased PFC activity to levels comparable to the control group. Also, viral-inhibition of Dyrk1A specifically in the PFC restored CSDS-induced depressive-like behavior, while Dyrk1A overexpression resulted in pronounced depressive symptoms even under subthreshold stress conditions. Moreover, episodic memory measurement via what-where-when task, revealing that increased Dyrk1A expression led to severe cognitive impairment and depressive-like behaviors, which were alleviated by Dyrk1A inhibition. Interestingly, in female mice, Dyrk1A overexpression induced depressive-like behavior but did not elicit cognitive impairment, suggesting a potential sex-specific role of Dyrk1A. Finally, we demonstrated that Dyrk1A facilitates the recruitment of RNAP II to the MAO-A promoter, promoting the transcription of MAO-A and subsequent serotonin degradation, resulting in depressive symptoms and cognitive impairment